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[(th)18.5(e)-400.9(c)0(o)13.8(m)0(p)17.7(l)0(e)11(x)0(i)18.5(t)0(y)-391.2(o)0(f)-390.5(h)0(u)15.5(m)0(a)10.2(n)-399.1(im)14.9(mu)17.7(ne)-396(su)20(rv)13.6(ei)16.7(ll)15.7(an)13.8(ce)-392.1(ca)12(n)-399.1(r)0(e)17.5(s)0(u)14.4(l)0(t)-394(i)0(n)-391.3(i)0(m)14.9(m)0(u)17.7(n)0(e)-396(r)0(e)17.5(a)0(c)17.7(t)0(i)15.7(o)0(n)15.5(s)-400.3(ev)13.8(en)-390.3(ag)13.8(ai)16.7(ns)14.4(t)-401.9(e)0(x)13.8(o)0(g)21.2(e)0(n)13.8(o)0(u)15.5(s)0(l)17.3(y)]TJ 0 -1.2007 TD [(ad)13.8(mi)14.9(ni)18.5(st)17.3(er)11.8(ed)-196.8(hu)15.5(ma)10.2(n)-205.6(p)0(r)13.6(o)0(t)18.5(e)0(i)16.7(n)0(s)-201.9(\()0(K)15.3(e)0(s)12.6(s)0(l)17.3(e)0(r)-204.5(e)0(t)-199.6(a)0(l)16.7(.)0(,)-199.9(2)0(0)15.5(0)0(6)15.5(\))0(.)-202.3(R)0(e)14.7(g)0(a)13.8(r)0(d)19.3(l)0(e)16.7(s)0(s)-203.1(o)0(f)-202.7(a)-207.4(pr)13.6(ot)18.5(ei)11(n)19.3(s)-212.5(o)0(r)19.3(i)0(g)12.8(i)13.5(n,)-206(t)13.5(h)0(e)-202.5(a)0(B)14.7(I)0(R)-201.7(i)0(s)-204.7(f)0(u)19.3(n)0(d)15.5(a)0(m)10.2(e)0(n)19.4(t)0(a)11(l)0(l)21.4(y)]TJ T* 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[(Grafting)-9.9(-based)-512.1()48.5(humanizat)-12.6(ion)49.1()-509.2(strategi)-9.7(es)-505.3(simpl)-8.4(y)-507.2(swap)-510.7(segment)-10.7(s)-508.4(o)0(f)-504.3(a)-509(biother)-8.9(apeutic)-511.3(candi)-10.1(date)-510.2(for)]TJ -1.0015 -1.2007 TD [(compara)-10.5(ble)-462.1(segm)-9.6(ents)-464(of)-464.4(a)-463.5(homologo)-6.7(us)-463.7(human)-464.4(p)-6.5(rotein.)-463.8(Whi)-7.6(le)-461.3(partic)-10(ularly)-463.4(eff)-8(ective)-465(for)-467.2(deimmuni)-9.1(zing)]TJ T* [(therape)-9.7(utic)-283.5(antibodi)-10.5(es)-283.3(\(Jones)-289.6(et)-279.2(al.,)-285.7(1986,)-288(Hwang)-286.6(and)-288.6(Foote,)-286.8(2005\),)-285(these)-290.2(methodo)-7.7(logies)-286.2(are)-286.7(predica)-9.7(ted)-280(on)]TJ T* [(the)-388.1(availa)-9.8(bility)-391.2(of)-384.8(a)-389.5(homologo)-6.7(us)-389.7(human)-390.4(protei)-8.2(n)-382(a)0(s)-391.5(well)-389.9(as)-391.5(detailed)-395.3(knowled)-8.1(ge)-384.6(of)-390.5(underlying)-392.5(struct)-9.4(ure)]TJ 0 -1.195 TD [(functi)-8.2(on)-246.2(relat)-9.2(ionships)-8.3(.)-245.1(Non-)-9(immunog)-9.5(lobulin)-252.6(protei)-8.2(ns,)-247.8(which)-257(represe)-10.2(nt)-249(a)-252.9(rich)-248.6(b)-6.5(u)0(t)-249(largely)-255.4(untap)-8.4(ped)-248.8(reservoi)-11.9(r)]TJ 0 -1.2007 TD [(of)-288(prospect)-9.9(ive)-285.7(therape)-9.7(utic)-289.2(agents,)-291.3(often)-289.2(fail)-291.2(to)-283.1(mee)-9.4(t)-282.4(one)-288.6(or)-288(both)-290.3(of)-282.3(thes)-8.8(e)-281.4(cri)-8.8(teria.)-288.4(As)-285.5(a)-287.1(resu)-8(lt,)-286.3(there)-291(exists)-293.1(a)]TJ T* [(growin)-7.6(g)-268.2(need)-274.1(for)-273.7(mor)-7.8(e)-270(broadly)-273.6(appl)-7.6(icable)-277.2(protei)-8.2(n)-268.2(deimm)-9.7(unization)-274.8(methodo)-13.4(logies,)-275.2(and)-271.5(the)-274.3(developm)-10.3(ent)-274.3(of)]TJ T* [(such)-336.1(methods)-344.7(will)-333.9(undoubt)-8.1(edly)-337.7(spur)-336.3(further)-340.2(innov)-6.6(ations)-337.4(in)-334.3(disease)-345.9(treatment.)]TJ 1.0015 -1.2007 TD [(As)-496(note)-7.6(d)-495.8(above,)-508.5(the)-496.2(aB)-8(IR)-497.6(is)-500.6(driven)-500.5(by)-502.3(molecu)-8.7(lar)-498.2(reco)-8.6(gnition)-503(of)-498.6(immunog)-9.5(enic)-498.8(pept)-7.6(ides,)-498.6(here)-8.6(after)]TJ -1.0015 -1.2007 TD [(epitope)-8.7(s,)-332.4(which)-336.7(are)-337.9(found)-341.5(within)-335.5(the)-336.9(biother)-8.9(apeutics)-339.6(pri)-7(mary)-334.7(seque)-8.6(nce.)-336.3(Immun)-7.2(e)-332.6(surve)-8.8(illance)-337.7(is)-335.5(initiat)-9.5(ed)]TJ T* [(when)-401.4(antigen)-8.7(-presenti)-9.7(ng)-394.2(cells)-401.1(internalize)-404.1(the)-399.5(therape)-9.7(utic)-397.3(protei)-8.2(n,)-393.8(which)-399.2(is)-398.1(then)-400.2(hydrolyze)-9.5(d)-393.4(into)-401.2(smaller)]TJ T* [(peptide)-441.2(fragme)-9.9(nts.)-433.4(Fragment)-11.5(s)-434.4(that)-437.2(represe)-10.1(nt)-431.1(pote)-7.6(ntial)-435(antigen)-8.7(ic)-438.6(epitopes)-437.5(are)-440.3(loaded)-437.7(into)-435.4(the)-439.3(groove)-440.8(of)]TJ 0 -1.195 TD [(cognate)-411.8(type)-411.6(II)-403.8(major)-412.2(histoco)-8.2(mpatibili)-8.9(ty)-402.6(com)-7.6(plex)-405.9(\()-88.1(MHC)-405.5(II\))-406.6(p)-6.5(roteins)-408.5(\(Fig)-7(.)-404.4(1A\),)-406.9(and)-408.1(the)-405.2(com)-7.6(plexes)-410.4(are)]TJ 0 -1.2007 TD [(trafck)-9.2(ed)-299.2(to)-300.2(the)-302.7(cell)-302.4(surf)-8.2(ace)-303.6(for)-302.1(display)-304.1(to)-300.2(the)-302.7(extrace)-11.5(llular)-301.2(milieu.)-308.8(There,)-305.5(the)-302.7(peptide)-8.7(MHC)-303.9(II)-301.4(comple)-8.7(xes)]TJ T* [(are)-343.6(free)-340.6(to)-340(interact)-346.1(with)-342.6(T-cell)-345.5(recepto)-9.7(r)-338.5(proteins)-346.6(on)-337.3(the)-342.6(surface)-345.9(of)-339.2(T-cell)-345.5(lymphoc)-7.7(ytes,)-339.2(and)-345.5(true)-339.6(immu)-7.2(no-)]TJ T* [(genic)-306.1(epitope)-8.7(s)-303.6(are)-309.4(recog)-9.4(nized)-306.1(upon)-304.7(format)-10.9(ion)-306.7(of)-305.1(ternary)-305.8(pept)-7.6(ideMH)-9.3(C)-301.4(IIT-)-9.6(cell)-308.1(recepto)-9.8(r)-298.6(com)-7.6(plexes.)-308.4(Th)-7(e)]TJ T* [(subse)-8(quent)-349.8(sign)-7(aling)-352.6(casc)-9.6(ade)-353(leads)-358.5(to)-351.4(maturation)-360.7(and)-351.2(prolif)-8.4(eration)-357.8(of)-350.6(B-cell)-356.1(lymphoc)-7.7(ytes)-355.9(that)-351.8(ultim)-9.9(ately)]TJ T* [(secret)-10.2(e)-332.6(immu)-7.2(noglobulin)-340.3(molecu)-8.7(les)-338.1(able)-333.7(to)-334.3(bind)-341.6(the)-331.2(o)-6.5(riginal)-336.1(biother)-8.9(apeutic)-340.6(agent.)]TJ 1.0015 -1.2007 TD [(This)-342.6(well-den)-9.7(ed)-344.8(immunolo)-7.3(gical)-343(path)-7.6(way)-343.8(suggests)-344.3(that)-346.1(therape)-9.7(utic)-340.4(prot)-7.8(eins)-338.8(mi)-7.8(ght)-340.8(be)-339.1(engi)-7.6(neered)-347.7(such)]TJ -1.0015 -1.2007 TD [(that)-249.4(their)-252.1(peptide)-253.4(fragments)-255.2(would)-249.5(evade)-253.9(MHC)-251.9(II/T-c)-9.2(ell)-248.6(recepto)-9.7(r)-241.7(bindi)-9.3(ng)-246.2(and)-248.8(thereby)-252.6(block)-253.1(the)-245.8(undesira)-9.9(ble)]TJ 0 -1.195 TD [(aBIR)-380.4(\(De)-379.9(Gr)-7.4(oot)-374.9(et)-381.7(al.,)-376.7(2005,)-379(De)-382.8(Groot)-382.4(and)-379.7(Martin,)-380.4(2009\).)-381.7(Indee)-9.4(d,)-376.7(the)-376.7(mutat)-9(ion)-374.9(of)-379.1(key)-379.7(anchor)-385.7(residue)-9.1(s)]TJ 0 -1.2007 TD [(within)-796.4(know)-7(n)-791.8(epitopes)-796(of)-794.5(therape)-9.7(utic)-795.7(proteins)-796.2(has)-796.3(yielded)-799.7(partially)-797.4(deimm)-9.7(unized)-796.2(versions)-800.3(of)]TJ ET q 432.17 0 0 116.674 107.603 173.537 cm /Im1 Do Q BT /F2 1 Tf 8.9663 0 0 8.9663 107.6031 157.6062 Tm [(FIG.)-246.3(1.)]TJ /F1 1 Tf 4.0277 0 TD (EpiSweep.)Tj /F2 1 Tf 4.5588 0 TD (\(A\))Tj /F1 1 Tf 1.6313 0 TD [(An)-248.9(immune)-250.8(response)-246.2(to)-249.6(a)-248.5(therapeutic)-252.9(protein)-243.6(is)-250.8(initiated)-248.2(by)-251.9(MHC)-247.5(II)-244.5(\(red/white\))-250.3(recognition)-254.4(of)]TJ -10.2178 -1.2266 TD [(an)-361.8(immunogenic)-362.3(peptide)-357.2(epitope)-363.5(\(blue\))-362.8(digested)-364.2(from)-360.9(the)-359.1(protein.)-360.3(Our)-358.5(goal)-364.9(is)-358.3(to)-363.4(mutate)-361.2(the)-359.1(protein)-363.7(so)-360.6(that)-356.3(no)-359.4(such)]TJ 0 -1.2203 TD [(recognition)-248.1(will)-253.7(occur.)]TJ /F2 1 Tf 9.3579 0 TD (\(B\))Tj /F1 1 Tf 1.5871 0 TD [(MHC/T-cell)-250.8(epitopes)-250.4(are)-252.6(pervasive:)-254.5(exposed)-249.2(on)-251.9(the)-245.2(surface,)-253.4(buried)-252.7(in)-249.6(the)-251.6(core,)-248.7(and)-247.5(covering)]TJ -10.945 -1.2203 TD [(active)-322.2(sites.)-329.5(Shown)-321.9(is)-320.4(staphylokinase)-331(\(PDB)-323.4(ID)-321.1(2sak\),)-322.8(with)-325.5(black)-322.6(backbone)-325.8(for)-326.2(no)-321.5(epitopes)-326.3(starting)-324.2(at)-321.6(the)-327.4(residue)-319.1(and)]TJ T* [(highlighted)-240.8(sausage)-240.2(for)-237.7(the)-238.9(predicted)-247.5(binding)-238.6(by)-239.3(eight)-235.6(common)-240.5(MHC)-241.2(II)-238.2(alleles,)-241.3(ranging)-239.6(from)-240.7(thin)-240(pale)-240.9(yellow)-238.5(\(bind)-238.1(just)]TJ 0 -1.2266 TD [(one\))-268.6(to)-268.6(thick)-267.3(bright)-273.3(red)-269.1(\(bind)-269.7(all)-268.2(eight\).)-272.3(Putative)-264.5(active)-271.6(sites)-276(are)-265.2(denoted)-271(with)-268.6(green)-270.6(arrows.)]TJ /F2 1 Tf 37.1218 0 TD (\(C\))Tj /F1 1 Tf 1.6566 0 TD [(EpiSweep)-272.2(explores)-268(the)]TJ -38.7784 -1.2203 TD [(Pareto)-260(frontier)-254.6(simultaneously)-260.3(optimizing)-257.4(structure)-261.5(\(molecular)-259.4(mechanics)-260.6(energy)-257.4(function,)]TJ /F5 1 Tf 36.7298 0 TD (y)Tj /F1 1 Tf .4489 0 TD [(-axis\))-256.5(and)-253.9(immunogenicity)]TJ -37.1787 -1.2203 TD [(\(epitope)-264.5(score,)]TJ /F5 1 Tf 6.1838 0 TD (x)Tj /F1 1 Tf .4426 0 TD [(-axis\).)-265.7(The)-266.3(left)-264(circled)-267.4(plan)-263.7(has)-267.7(fewer)-263.8(predicted)-266.4(epitopes)-269.4(than)-263.7(the)-264.2(right)-261.1(one,)-263.1(but)-268.1(the)-264.2(right)-261.1(one)-266.5(has)-261.4(better)]TJ -6.6264 -1.2266 TD [(predicted)-336(energy.)-336.2(MHC)-336(II,)-329.6(type)-333.3(II)-333(major)-338.9(histocompatibility)-336.4(complex;)-335(PDB,)-330.5(Protein)-337(Data)-339(Bank.)]TJ /F2 1 Tf 9.9626 0 0 9.9626 107.6031 737.4045 Tm [(PROT)-9.3(EIN)-336.5(DEIM)-9.7(MUNIZAT)-13.2(ION)-27359.7(153)]TJ ET endstream endobj 4 0 obj <>stream Adobed         s!1AQa"q2B#R3b$r%C4Scs5D'6Tdt& EFVU(eufv7GWgw8HXhx)9IYiy*:JZjzm!1AQa"q2#BRbr3$4CS%cs5DT &6E'dtU7()󄔤euFVfvGWgw8HXhx9IYiy*:JZjz ?i-jzLۗv; U_WGa75&Ep2QAe&'z]v*UثWb]8kStz/~Q ت_YE }b޽>x9oc2FiuqWb]v*UثWb]v*UثWb]aߜ>cռiDan$d E]ՁSw^{rYim^4V'h|H{~n5*y(|+4㊿ 2,U؏꽧v*UثWb]v*UثWyr{i5; YUaRjO?/?-{o e ^ק:W3ͬÔSD#Db]v*UثWb]v*UثWbX$yCQ.HlPSFW!"I ⯟VcStYΛb U8vZ9H¿,U~B~syz9Z->FgEdOJNH 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[(im)-7.8(portant)-316.2(to)-317.3(note)-314.9(that)-317.6(unlike)-319.2(antibody)-320.7(epitope)-8.7(s,)-309.6(which)-319.6(loca)-9.4(lize)-313.7(excl)-9.4(usively)-315.4(to)-317.3(the)-314.1(solv)-7(ent-expo)-8.7(sed)-312.6(prot)-7.8(ein)]TJ 0 -1.2007 TD [(surf)-8.2(ace,)-321(T-cell)-322.7(epitope)-8.7(s)-314.9(resu)-8(lt)-314.3(from)-323.5(proteol)-8.9(ytic)-317.6(proce)-9.4(ssing)-321.9(and)-317.1(may)-320.6(theref)-9.2(ore)-319(be)-316.3(found)-324.5(anywher)-9.1(e)-315.5(within)-324.1(a)]TJ T* [(prot)-7.8(eins)-341.6(primary)-341.7(seque)-8.6(nce)-335.9(\(Fig)-7(.)-336.1(1B\).)-339.4(As)-336.7(a)-338.3(resu)-8(lt,)-337.5(experiment)-12.6(al)-336.1(determ)-10.7(ination)-339.8(of)-339.2(T-cell)-345.5(epitope)-8.7(s)-332(requi)-10.3(res)]TJ T* [(tec)-8.6(hnically)-422(challengin)-9.9(g)-410.5(immu)-7.2(noass)-8(ays)-415(on)-411.2(lar)-8.8(ge)-413(pools)-417.5(of)-413.2(overlapp)-8.7(ing)-414.8(com)-7.6(ponent)-418.8(peptides)-420.4(that)-414.4(span)-421.4(the)]TJ T* [(entire)-357.1(protein)-350.4(of)-344.9(intere)-10(st.)-347.3(Upon)-348.4(iden)-7.6(tifying)-351.3(the)-348.3(immu)-7.2(nodomina)-8.5(nt)-345.7(peptide)-8.7(s,)-343.8(the)-354(protein)-350.4(engineer)-357.6(then)-349(per-)]TJ T* [(forms)-439.3(scann)-8.6(ing)-431.8(alanine)-437.3(or)-430.3(othe)-7.6(r)-429.5(system)-9.3(atic)-433.3(mutage)-8.7(nesis)-437.5(on)-428.3(each)-440.9(one)-430.9(so)-435.2(as)-431.3(to)-431.1(identify)-439.3(critica)-9.6(l)-430.3(binding)]TJ T* [(residue)-9.1(s)-337.7(whose)-340.8(substitut)-8.9(ion)-335.1(ameliora)-11.1(tes)-332.4(the)-336.9(undesi)-10.3(red)-336.1(immun)-7.9(e)-332.6(response.)-344.5(Efcaciou)-10.3(s)-332(mut)-8.6(ations)-337.4(must)-334.9(then)]TJ T* [(be)-356.1(engineer)-10.5(ed)-350.4(back)-353.7(into)-350(the)-354(full-)-7.6(length)-353.3(protei)-8.2(n,)-348.3(where)-354.7(they)-354.7(often)-357.5(affect)-352.4(struct)-9.4(ural)-351(sta)-8(bility)-351.4(or)-350.6(therape)-9.7(utic)]TJ 0 -1.195 TD [(funct)-10.3(ion.)-432.2(For)-430.3(exampl)-8.7(e,)-429.7(hydrop)-6.6(hobic)-435.2(amino)-433(acids)-438.1(typically)-436.9(anchor)-436.9(peptide)-435.5(epitope)-8.7(s)-428.8(within)-437.9(the)-427.9(MH)-7.4(C)-432.3(I)0(I)]TJ 0 -1.2007 TD [(bindi)-9.3(ng)-263.3(groove)-8.3(,)-262.1(and)-265.8(these)-267.4(amino)-268(aci)-8.6(ds)-264.5(therefore)-271.3(represe)-10.1(nt)-266.1(attractive)-272.5(targets)-268(for)-268(mutage)-8.7(nic)-268.6(epitope)-270.5(deletion.)]TJ T* [(Th)-7(ose)-289.8(sam)-8.8(e)-292.8(residue)-9.1(s,)-286.9(h)-6.5(owever,)-299(can)-290.4(als)-8(o)-291(play)-292.1(a)-292.8(central)-302.7(role)-294.1(in)-288.8(sta)-8(bilizing)-297.8(the)-291.4(close-p)-9.1(acked)-299.4(core)-293.1(of)-293.7(the)-297.1(full-)]TJ T* [(leng)-7.6(th)-357.1(protein,)-362.1(and)-356.9(substitut)-8.9(ion)-357.9(at)-353.2(these)-364.2(positions)-359(may)-360.4(comprom)-10.5(ise)-355.2(protei)-8.2(n)-353.6(folding)-7.1(.)-353.2(Intuitiv)-7.7(ely,)-360(deimmu-)]TJ T* [(nizing)-387.5(mutation)-8.3(s)-377.5(mus)-7(t)-379.1(not)-380.6(under)-7.6(mine)-381(the)-382.4(target)-385.5(protein)-8.9(s)-380.3(native)-383.6(structure)-385.3(or)-384.8(function,)-385.7(and)-379.7(conse)-8.6(quently)]TJ T* [(prot)-7.8(ein)-336.9(deimmuni)-9.1(zation)-338(is)-335.5(inherent)-11.5(ly)-334.3(a)-332.6(multi-o)-7.7(bjective)-344.1(optimiza)-10.1(tion)-332.9(probl)-8.6(em.)]TJ 1.0015 -1.2007 TD [(To)-462.3(efci)-11.3(ently)-466.4(direct)-465.2(exper)-9.4(imental)-470.3(resources)-468.1(towar)-8.6(d)-461.7(the)-462.1(mos)-7(t)-458.8(p)-6.5(romising)-467.9(sets)-465.2(of)-464.4(mutation)-8.3(s,)-463.3(we)-462.5(have)]TJ -1.0015 -1.2007 TD [(devel)-10.1(oped)-363.3(EpiSweep)-9.7(,)-358.9(a)-366.7(novel)-361.2(appro)-7.6(ach)-364.4(that)-363.2(integr)-8.2(ates)-363.4(validated)-373.3(immunoin)-7.3(formati)-8.7(cs)-363(and)-362.6(structura)-9.7(l)-362(mod-)]TJ 0 -1.195 TD [(eling)-301.3(methods)-299.1(within)-295.6(a)-292.8(fra)-8(mework)-300.3(for)-290.8(iden)-7.6(tifying)-294.4(Pareto)-302.3(optimal)-297.8(designs)-302.5(\(Fig.)-291.9(1C\).)-299.6(These)-298.6(designs)-296.8(\(sets)-297.2(of)]TJ 0 -1.2007 TD [(mut)-8.6(ations\))-294.7(mak)-7.6(e)-292.8(the)-297.1(best)-293.3(trade-)-9.2(offs)-292.7(betwee)-10.9(n)-291(the)-297.1(two)-293.5(obje)-7.6(ctives)-299.4(of)-293.7(stability)-296.8(and)-300(immunogeni)-10.6(city)-294.9(in)-294.5(that)-294.9(no)]TJ T* [(desi)-8.8(gn)-291.7(is)-290(simul)-8.4(taneousl)-10.7(y)-291(better)-294.5(for)-296.5(both)-296(objectives)-11.1(.)]TJ /F5 1 Tf 20.9924 0 TD [(\(Stabili)-7.7(ty\))]TJ /F1 1 Tf 4.3191 0 TD [(We)-296.1(compute)-299.7(protei)-8.2(n)-291(stability)-296.8(usin)-7(g)-291(a)-292.8(highly)]TJ -25.3116 -1.2007 TD [(succe)-10.4(ssful,)-318.6(structure)-9.7(-based)-318.6(prot)-7.8(ein)-314.1(desig)-9.6(n)-313.7(strategy)-320(that)-317.6(seeks)-322.8(to)-311.6(optim)-7.2(ize)-315.9(side-ch)-9.1(ain)-314.1(packi)-10.1(ng)-314.5(\(Dahi)-8.6(yat)-314.1(and)]TJ T* [(Mayo,)-286(1997;)-279.7(Lilie)-8(n)-273.9(e)0(t)-279.2(al.,)-280(2004;)-279.7(Chen)-282.7(et)-279.2(al.,)-274.3(2)-6.5(009\).)-278.6(In)-276.7(this)-277.2(appro)-7.6(ach,)-279.4(the)-280(prot)-7.8(ein)-274.3(backbo)-8.2(ne)-282.2(is)-278.6(xed,)-277.6(and)-282.9(the)]TJ T* [(best)-424.2(side-chain)-425.7(conform)-8.9(ations)-417.1(\(allow)-12.1(ing)-414.8(for)-416(amino)-421.6(acid)-419.1(subsi)-9(tutions\))-421.6(are)-417.6(chose)-8.6(n)-410.5(from)-420.3(a)-418(discrete)-424.2(set)-417.7(of)]TJ T* [(com)-7.6(mon,)-273.6(low-e)-8.6(nergy)-275(rotam)-8.2(ers.)-275.1(Individ)-7.2(ual)-274.3(rotamers)-277.2(are)-275.3(select)-11(ed)-270.8(so)-275.9(as)-272(to)-271.7(minimi)-8.5(ze)-272.6(the)-274.3(total)-275.7(protei)-8.2(n)-268.2(ener)-8.6(gy,)]TJ T* [(cal)-8.6(culated)-346.3(with)-342.6(a)-338.3(molecu)-8.7(lar)-344.6(mechanics)-345.8(ener)-8.6(gy)-337.3(functi)-8.2(on.)-343.3(The)-339.6(side-ch)-9.2(ain)-342.6(packing)-347.4(approach)-343.5(assum)-11.5(es)-340.3(that)-340.4(a)]TJ 0 -1.195 TD [(desi)-8.8(gn)-360(with)-365.3(low)-361.8(ener)-8.6(gy)-360(for)-359.1(the)-365.3(xed-tar)-9.9(get)-359.6(backbo)-8.2(ne)-361.8(will)-368.1(in)-357.1(fact)-369.9(adopt)-361.2(that)-363.2(target)-368.5(backbo)-8.2(ne.)-362.2(While)-366.5(this)]TJ 0 -1.2007 TD [(assum)-11.5(ption)-402(has)-403.6(been)-405(borne)-405.9(out)-403.4(by)-405.6(the)-399.5(exper)-9.4(imental)-407.7(demo)-8.4(nstration)-407.1(of)-401.8(stable)-9.2(,)-398.7(active)-408.1(protei)-8.2(ns,)-401.4(it)-399.7(may)-405.9(be)]TJ T* [(advant)-10.9(ageous)-498.7(to)-488(it)-7.1(erate)-497.6(xed-backbo)-9.2(ne)-492.7(desi)-8.8(gn)-490.9(with)-496.2(structure)-499.1(predict)-10.7(ion,)-489.1(as)-493.9(is)-494.9(done)-494.2(in)-493.7(Roset)-8.6(taDesign)]TJ T* [(\(K)-7.4(uhlman)-268.7(and)-265.8(Ba)-8(ker,)-262.5(200)-8(0\),)-265.6(in)-260.4(order)-271.3(to)-266.1(assess)-269(whe)-8(ther)-265.6(the)-268.6(designed)-275.4(sequence)-270.5(is)-267.2(likely)-270.7(to)-266.1(adopt)-264.4(the)-268.6(desired)]TJ T* [(backbo)-8.1(ne)-424.4(confo)-7.6(rmation.)]TJ /F5 1 Tf 10.3625 0 TD [(\(Imm)-9.2(unogenici)-10.3(ty\))]TJ /F1 1 Tf 7.5627 0 TD [(To)-422.4(assess)-428.3(immu)-7.2(nogenici)-9.5(ty,)-420.1(we)-428.3(leverag)-9.7(e)-418(the)-427.9(well-es)-10.1(tablished)]TJ -17.9252 -1.2007 TD [(devel)-10.1(opment)-280.1(of)-276.6(T-cel)-11.9(l)-271(epitope)-287.6(predictors)-283.6(that)-283.5(encapsul)-9.7(ate)-276.1(the)-280(under)-7.6(lying)-276.8(speci)-11.3(c)-275.7(reco)-8.6(gnition)-281.1(of)-276.6(an)-276.5(epitope)]TJ T* [(by)-479.5(an)-481.3(MH)-7.4(C)-477.8(I)0(I)-477.8(prot)-7.8(ein)-479.2(\(De)-482.3(Groot)-484.8(and)-482.1(Moise,)-484.2(2007\).)-478.5(MH)-7.4(C)-477.8(I)0(I)-483.5(proteins)-483.2(from)-482.8(the)-479.2(predo)-7.6(minant)-482(huma)-8.4(n)]TJ T* [(leuk)-7.6(ocyte)-431.2(antigen)-429.8(DR)-425.6(isotype)-434.9(\(HLA-DR\))-432.4(h)-6.5(ave)-427(a)-423.7(reco)-8.6(gnition)-429(groove)-429.4(whose)-431.8(pockets)-428.3(form)-431.6(energet)-9.7(ically)]TJ 0 -1.195 TD [(favor)-9.6(able)-259.8(interactions)-262(with)-257.2(speci)-11.3(c)-252.9(side-ch)-9.1(ains)-259.2(of)-253.9(peptide)-8.7(s)-252.3(appro)-7.6(ximatel)-9.3(y)-251.2(nine)-258(residue)-9.2(s)-252.3(i)0(n)-254.7(leng)-7.6(th)-254.7(\(Fig.)-257.8(1A\).)]TJ 0 -1.2007 TD [(Num)-9.7(erous)-344.5(compu)-9.1(tational)-345.1(methods)-350.3(are)-349.3(available)-352.3(for)-342(identifyi)-10.3(ng)-343(peptide)-344.5(epitop)-11.9(es,)-340.6(and)-345.5(stud)-7(ies)-343.8(have)-342.4(show)-8.2(n)]TJ T* [(thes)-8.8(e)-321.2(methods)-327.6(to)-317.3(be)-322(predict)-10.7(ive)-319.8(of)-322.2(immu)-7.2(nogenici)-9.5(ty)-317.3(\(Wa)-8.6(ng)-320.2(et)-319.1(al.,)-325.5(2008,)-322.1(De)-325.9(Groot)-319.8(and)-322.7(Mar)-8(tin,)-321.2(2009\).)-324.8(Here)]TJ T* [(we)-337.3(asse)-9(ss)-334(each)-338.5(const)-9.6(ituent)-339(peptide)-338.8(of)-333.6(our)-334.3(prot)-7.8(ein)-336.9(and)-334.1(optim)-7.2(ize)-338.7(the)-331.2(tot)-7.8(al.)]TJ 1.0015 -1.2007 TD [(Epi)12.2(Swe)9.9(ep)-487(is)-483.5(the)-484.8(rs)12.4(t)-487.2(pro)12.8(tei)13.2(n)-490.2(des)11.8(ign)-483.1(too)12(l)-487.2(tha)10.2(t)-487.2(sim)13(ulta)12.4(neo)13(usl)10.8(y)-490.2(opt)17.7(imi)11.4(zes)-485.1(prim)17.1(ary)-484.1(seq)11.8(uen)13(ce,)-483.5(red)11(uci)10.2(ng)]TJ -1.0015 -1.2007 TD [(imm)10.7(unog)14(eni)10.2(cit)13.2(y)-302.4(and)-288.6(tert)10.4(ia)11(ry)-299.4(st)11.6(ruc)11(ture)13.2(,)-296.3(main)11.6(tai)13.2(nin)12(g)-302.4(s)0(t)11.6(abi)10.2(lit)12.2(y)-302.4(and)-288.6(func)10.3(tio)14.9(n.)-297.1(It)-296.5(si)11.6(gni)12(can)11.2(tly)-292.3(ext)15.9(ends)-290.6(stru)13.8(ct)11(ure)11(-)]TJ T* [(base)9.3(d)-262.5(pro)12.8(te)11(in)-260.4(des)11.8(ign)-255.4(by)-257.6(acc)9.4(ount)11.3(in)12.8(g)-262.5(for)-256.6(the)-257.2(comp)14.4(le)11(ment)11.6(ary)-256.4(goa)13(l)-265.3(o)0(f)-259.6(imm)10.7(uno)14.8(gen)13(icit)15.3(y.)-262.9(It)-256.7(lik)14.9(ewis)10(e)-264.3(s)0(i)11.6(gni)12(can)11.2(tly)]TJ T* [(ext)10.2(ends)-250.7(our)-254.6(pre)11(vio)12(us)-258.8(work)-253.7(on)-257.6(Par)11.8(eto)-257.2(opt)12(imi)11.4(zati)16.3(on)-263.3(for)-250.9(pro)12.8(tein)-255.1(eng)13(ine)10.2(eri)14(ng)-263.3(in)-254.7(gene)10.4(ra)11.8(l)-265.3(\(Zh)13(eng)-254.5(et)-262.1(al.)10.6(,)-262.1(200)14.8(9,)-257.2(He)]TJ 0 -1.195 TD [(et)-370.3(al.)10.6(,)-370.3(2012)14(\))-372.6(and)-368.3(for)-364.7(dei)15.9(mmun)12.7(izat)16.3(ion)-369.3(in)-368.5(par)11(tic)13.2(ula)10.2(r,)-367.3(whi)13.8(ch)-373.2(ass)10.6(ess)10.6(ed)-367.5(effe)12.2(ct)11(s)-371.8(o)0(n)-371.4(str)14.5(uct)10.2(ure)-364.6(and)-368.3(fun)12.8(cti)13.2(on)-371.4(onl)12(y)]TJ 0 -1.2007 TD [(acc)9.4(ordi)15(ng)-257.6(to)-260.4(a)-264.3(seq)11.8(uenc)10.4(e)-258.6(pot)12(ent)10.2(ial)-254.3(\(Par)14.8(ker)-256.4(et)-262.2(al)11(.,)-262.5(201)14.8(0;)-260.4(Par)11.8(ker)-256.4(et)-256.5(al.)10.6(,)-262.1(2011)14(a,)-259(Par)11.8(ker)-256.4(et)-262.2(al)11(.,)-256.8(2011)14(b\).)-254.3(Ins)11.6(pire)13.2(d)-262.5(b)0(y)]TJ T* 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[(prod)12(uce)-222.1(nea)11.2(r-o)10.8(pti)15(mal)-226.6(pla)10.2(ns.)-219.3(Alt)11(houg)14(h,)-223.1(bey)13(ond)-224.2(the)-223.1(sco)11.8(pe)-225.2(of)-231.1(th)12.8(is)-227.4(arti)16.1(cle,)-219.6(Epi)12.2(Swe)9.8(ep)-230.9(pro)12.8(mis)13(es)-226.4(to)-226.2(info)15(rm)-229(pr)13.6(ote)10.2(in)]TJ T* [(engi)15.2(neer)14.2(ing)-227(exp)13(erim)9.7(ent)15.9(s)-235.3([as)-229.2(our)-226.2(seq)11.8(uen)13(ce-)9.2(bas)11.8(ed)-230.9(alg)10.2(orit)17.9(hms)-228.9(hav)13(e)-235.9(done)-221.1(\(Osi)15.5(povi)11.3(tc)11(h)-234.1(e)0(t)-233.7(a)0(l)11(.)0(,)-228.4(2012)14(\)])-233.1(see)10(ki)12.8(ng)-234.8(se)12.6(ts)]TJ T* [(of)-327.9(effe)12.2(ct)11(ive)-319.8(dei)10.2(mmun)12.7(izi)13.2(ng)-325.9(muta)11.6(tio)14.9(ns)-327.1(for)-319.2(the)-319.8(deve)10.4(lo)12.8(pmen)14.4(t)-333.6(o)0(f)-322.2(enh)13(anc)11.2(ed)-327.7(bio)12(the)10.2(rap)11(eut)10.2(ic)11(s.)]TJ /F2 1 Tf 10.959 0 0 10.959 254.4944 105.789 Tm [(2.)-496.7(METHODS)]TJ /F1 1 Tf 9.9626 0 0 9.9626 84.0755 81.8646 Tm [(We)-370.1(seek)-372(to)-368.5(make)-368.7(mutat)-9(ions)-365.5(to)-368.5(a)-366.7(target)-374.2(protei)-8.2(n)-365(s)0(o)-366.9(a)0(s)-368.7(t)0(o)-368.5(reduce)-370.4(its)-373.2(immunogeni)-10.6(city,)-369.2(as)-368.7(evaluat)-10.5(ed)-367.5(by)-365.7(a)]TJ -1.0015 -1.2007 TD [(seque)-8.6(nce-)-8.6(based)-259(epitope)-264.8(score,)-261.3(while)-259.7(maintai)-9.3(ning)-256.2(its)-259.4(stability)-262.7(and)-260.2(activity)-9.3(,)-250.8(a)0(s)-260.6(evaluated)-264.2(by)-257.6(a)-258.6(structure)-9.7(-based)]TJ /F2 1 Tf 0 67.0005 TD [(15)-7.2(4)]TJ 35.3326 0 TD [(PAR)-10(KER)-338.8(ET)-335.3(AL.)]TJ ET endstream endobj 8 0 obj <> endobj 9 0 obj <>/ProcSet[/PDF/Text]/ExtGState<>>> endobj 10 0 obj <>stream /GS1 gs BT /F1 1 Tf 9.9626 0 0 9.9626 107.6031 715.4644 Tm 0 0 0 rg 0 Tc 0 Tw [(effective)-495.8(ener)-8.6(gy)-485.2(functi)-8.2(on.)-485.6(We)-489.6(now)-489.9(formali)-8.7(ze)-488.8(this)-487.8(as)-488.2(a)-486.3(Pareto)-495.8(optimiza)-10.1(tion)-486.6(problem)-493.4(that)-488.4(exte)-9.4(nds)-487.2(the)]TJ 0 -1.195 TD [(standar)-9.1(d)-302.4(side-ch)-9.1(ain)-302.7(packing)-307.6(formul)-9.1(ation)-307(of)-299.4(struct)-9.4(ure-base)-10.9(d)-302.4(protein)-304.8(desig)-9.6(n)-296.7(\()0(D)-7.4(ahiyat)-303.9(and)-305.7(Mayo,)-308.8(1997\))-307.4(with)]TJ 0 -1.2007 TD [(the)-245.8(comple)-8.7(mentary/)-9.3(compet)-8.7(ing)-238.4(epitop)-11.9(e)-241.6(score.)-244.2(In)-248.2(general,)-249.1(structure)-9.7(-based)-250.3(protein)-247.9(design)-243.6(probl)-8.6(ems)-242.1(have)-251.3(been)]TJ T* [(shown)-339(to)-334.3(be)-333.4(NP-)-7.4(hard)-336.9(\(Pierce)-341(and)-339.8(Winfree,)-342.9(2002\).)]TJ /F2 1 Tf 1.0015 -2.151 TD [(Problem)-400.4(1)-399.1(\(Structur)-10.1(ally)-395.5(Guid)-7.8(ed)-395.2(Deim)-8.6(munization)-11.6(\))]TJ /F5 1 Tf 22.3582 0 TD [(We)-398.7(are)-397.9(give)-9.4(n)-393.4(a)-393.4(protein)-400.8(seque)-8.6(nce)-398.5(A)-393.2(o)0(f)-396.9(n)-393.4(amino)]TJ -23.3597 -1.2007 TD [(acids,)-305.8(along)-302.5(with)-303.5(a)-302.4(3)0(D)-301.4(struct)-8.6(ure)-301.2(that)-304.5(include)-8.7(s)-297.9(a)-302.4(backbon)-8.9(e)-298.5(a)0(s)-298.6(w)0(e)-8(l)0(l)-297.3(a)0(s)-304.3(a)-296.7(rota)-7(mer)-305.1(sequence)-310.3(R)-302.2(paralleli)-9.5(ng)-297.4(A.)]TJ T* [(We)-302(are)-301.2(also)-297.2(given)-306.1(a)-296.7(set)-298.2(M)-299.4(o)0(f)-300.2(mutabl)-8.3(e)-298.5(positions)-302.1(\(amino)-303.5(acid)-303.5(types)-301.6(allow)-8.4(ed)-299.2(to)-294.5(vary\))-10.6(,)-296.3(and)-298.2(a)-296.7(set)-303.9(F)-296.5(o)0(f)-300.2(exible)]TJ T* [(positions)-273.6(\(side-chai)-10.5(ns)-264.5(allowed)-273.4(to)-260.4(vary\))-272.3(with)-269.4(M)]TJ /F6 1 Tf 19.0235 0 TD ()Tj /F5 1 Tf 1.0357 0 TD [(F;)-265.1(by)-265.1(defa)-7.6(ult)-263.9(M)]TJ /F7 1 Tf 6.5271 0 TD (=)Tj /F5 1 Tf .7227 0 TD (F)Tj /F7 1 Tf .8194 0 TD (=)Tj /F6 1 Tf .7227 0 TD (f)Tj /F1 1 Tf .5008 0 TD (1)Tj /F8 1 Tf 1.1666 0 TD .1682 Tc (...)Tj /F1 1 Tf 1.3145 0 TD 0 Tc ()Tj /F5 1 Tf .5008 0 TD (n)Tj /F6 1 Tf .5008 0 TD (g)Tj /F1 1 Tf .5008 0 TD (.)Tj /F5 1 Tf .5121 0 TD [(Final)-9.1(ly,)-262.5(we)-269.8(are)-267(given)-266.2(a)]TJ -33.8474 -1.2007 TD [(mutat)-7.6(ional)-242.6(load)-244.8(m.)-244.1(Let)-245.1(a)]TJ /F1 1 Tf 10.1007 0 TD (design)Tj /F5 1 Tf 2.8567 0 TD [(be)-248(an)-240.5(m-mutat)-9.3(ion)-244.1(seque)-8.6(nce)-244.9(A)]TJ /F6 1 Tf 6.9738 0 0 6.9738 354.6707 613.9841 Tm (0)Tj /F5 1 Tf 9.9626 0 0 9.9626 357.0518 610.3557 Tm [(,)-245.1(with)-246.6(mutations)-247.9(only)-246.6(at)-243.3(positions)-250.8(in)-243.3(M,)-242.9(along)]TJ -25.0384 -1.195 TD [(with)-377.5(a)-370.7(set)-372.2(R)]TJ /F6 1 Tf 6.9738 0 0 6.9738 158.1732 602.0219 Tm (0)Tj /F5 1 Tf 9.9626 0 0 9.9626 164.296 598.4502 Tm [(of)-374.2(selected)-378.5(rota)-7(mers,)-375.7(diffe)-8.2(ring)-371.2(from)-375.1(R)-376.2(only)-371.8(at)-374.2(posi)-7(tions)-374.7(in)-374.2(F.)-370.8(Our)-377.3(goal)-375.7(is)-369.7(to)-374.2(determ)-10.3(ine)-371(all)]TJ -5.6905 -1.2007 TD [(Pareto)-340.2(optim)-7.6(al)-334.3(designs,)-337(min)-9(imizing)-337.4(the)-336.9(two)-334.1(ob)-7.2(jectives)]TJ 11.7453 -2.8851 TD (f)Tj /F9 1 Tf 6.9738 0 0 6.9738 227.3952 556.2708 Tm ()Tj /F10 1 Tf 9.9626 0 0 9.9626 230.6834 557.7448 Tm (\()Tj /F5 1 Tf .3244 0 TD (A)Tj /F6 1 Tf 6.9738 0 0 6.9738 240.0377 561.8266 Tm (0)Tj /F10 1 Tf 9.9626 0 0 9.9626 242.4188 557.7448 Tm (\))Tj /F7 1 Tf .4894 0 TD (=)Tj /F11 1 Tf .8877 .9446 TD (X)Tj /F5 1 Tf 6.9738 0 0 6.9738 256.7054 569.1967 Tm (n)Tj /F7 1 Tf .6666 0 TD (-)Tj /F1 1 Tf .7235 0 TD (8)Tj /F5 1 Tf -1.2763 -3.1867 TD (i)Tj /F7 1 Tf .4471 0 TD (=)Tj /F1 1 Tf .7154 0 TD (1)Tj /F9 1 Tf 9.9626 0 0 9.9626 272.1259 557.7448 Tm ()Tj /F10 1 Tf .3927 0 TD (\()Tj /F5 1 Tf .3244 0 TD (A)Tj /F6 1 Tf 6.9738 0 0 6.9738 285.4487 561.8266 Tm (0)Tj /F10 1 Tf 9.9626 0 0 9.9626 287.8298 557.7448 Tm ([)Tj /F5 1 Tf .3244 0 TD (i)Tj /F8 1 Tf .4439 0 TD .1682 Tc (...)Tj /F5 1 Tf 1.3145 0 TD 0 Tc (i)Tj /F7 1 Tf .4496 0 TD (+)Tj /F1 1 Tf .7227 0 TD (8)Tj /F10 1 Tf .5008 0 TD [(]\))-19563.1(\()]TJ /F1 1 Tf 20.5315 0 TD (1)Tj /F10 1 Tf .5008 0 TD (\))Tj /F5 1 Tf -31.133 -2.5323 TD (f)Tj /F12 1 Tf 6.9738 0 0 6.9738 227.3952 531.0424 Tm (/)Tj /F10 1 Tf 9.9626 0 0 9.9626 232.5543 532.5164 Tm (\()Tj /F5 1 Tf .3244 0 TD (R)Tj /F6 1 Tf 6.9738 0 0 6.9738 241.9086 536.655 Tm (0)Tj /F10 1 Tf 9.9626 0 0 9.9626 244.2897 532.5164 Tm (\))Tj /F7 1 Tf .4951 0 TD (=)Tj /F11 1 Tf .882 .9503 TD (X)Tj /F5 1 Tf 6.9738 0 0 6.9738 259.5968 521.9148 Tm (i)Tj /F6 1 Tf .2845 0 TD (2)Tj /F5 1 Tf .6585 0 TD (F)Tj /F12 1 Tf 9.9626 0 0 9.9626 273.9968 532.5164 Tm (/)Tj /F5 1 Tf 6.9738 0 0 6.9738 280.6865 530.2487 Tm (i)Tj /F10 1 Tf 9.9626 0 0 9.9626 283.1243 532.5164 Tm (\()Tj /F5 1 Tf .3244 0 TD (R)Tj /F6 1 Tf 6.9738 0 0 6.9738 292.4786 536.655 Tm (0)Tj /F10 1 Tf 9.9626 0 0 9.9626 294.8597 532.5164 Tm ([)Tj /F5 1 Tf .3244 0 TD (i)Tj /F10 1 Tf .2845 0 TD (]\))Tj /F7 1 Tf .8137 0 TD (+)Tj /F11 1 Tf .882 .9503 TD (X)Tj /F5 1 Tf 6.9738 0 0 6.9738 319.4645 521.9148 Tm (i)Tj /F6 1 Tf .2764 0 TD (2)Tj /F5 1 Tf .6585 0 TD (F)Tj /F11 1 Tf 9.9626 0 0 9.9626 338.6267 541.9841 Tm (X)Tj /F5 1 Tf 6.9738 0 0 6.9738 333.8078 521.4613 Tm (j)Tj /F6 1 Tf .2845 0 TD (2)Tj /F5 1 Tf .6585 0 TD (F)Tj /F1 1 Tf .6504 0 TD ()Tj /F5 1 Tf .504 0 TD (j)Tj /F6 1 Tf .2845 0 TD (6)Tj T* ()Tj /F5 1 Tf .7723 0 TD (i)Tj /F12 1 Tf 9.9626 0 0 9.9626 359.433 532.5164 Tm (/)Tj /F5 1 Tf 6.9738 0 0 6.9738 366.066 530.2487 Tm (i)Tj /F1 1 Tf .2845 0 TD ()Tj /F5 1 Tf .4959 0 TD (j)Tj /F10 1 Tf 9.9626 0 0 9.9626 374.0031 532.5164 Tm (\()Tj /F5 1 Tf .3244 0 TD (R)Tj /F6 1 Tf 6.9738 0 0 6.9738 383.3574 536.655 Tm (0)Tj /F10 1 Tf 9.9626 0 0 9.9626 385.7385 532.5164 Tm ([)Tj /F5 1 Tf .3244 0 TD (i)Tj /F10 1 Tf .2788 0 TD (])Tj /F1 1 Tf .3244 0 TD ()Tj /F5 1 Tf .5008 0 TD (R)Tj /F6 1 Tf 6.9738 0 0 6.9738 406.0912 536.655 Tm (0)Tj /F10 1 Tf 9.9626 0 0 9.9626 408.4723 532.5164 Tm ([)Tj /F5 1 Tf .3244 0 TD (j)Tj /F10 1 Tf .2845 0 TD [(]\))-10600.5(\()]TJ /F1 1 Tf 11.5689 0 TD (2)Tj /F10 1 Tf .5008 0 TD (\))Tj /F5 1 Tf -42.8783 -3.0046 TD [(based)-336.8(on)-337.3(the)-336.9(following)-341.3(contrib)-8.2(utions:)]TJ /F6 1 Tf 7.9702 0 0 7.9702 117.5811 485.9715 Tm ()Tj /F9 1 Tf 9.9626 0 0 9.9626 126.5385 484.6676 Tm ()Tj /F8 1 Tf .6715 0 TD (:)Tj /F6 1 Tf .552 0 TD (A)Tj /F1 1 Tf 6.9738 0 0 6.9738 146.6078 489.1463 Tm (9)Tj /F6 1 Tf 9.9626 0 0 9.9626 153.3543 484.6676 Tm (!)Tj /F13 1 Tf 1.2804 0 TD (N)Tj /F5 1 Tf 1.1609 0 TD [(gives)-335.7(the)]TJ /F1 1 Tf 3.9606 0 TD [(epitope)-344.5(score)]TJ /F5 1 Tf 5.7475 0 TD [(for)-336.3(a)-336.5(peptide)-338.8(\(we)-340.8(assume)-337(a)-336.5(9-mer;)-339.8(see)-337.1(belo)-7.6(w\).)]TJ /F6 1 Tf 7.9702 0 0 7.9702 117.5811 474.0093 Tm ()Tj /F12 1 Tf 9.9626 0 0 9.9626 126.5385 472.7054 Tm (/)Tj /F5 1 Tf 6.9738 0 0 6.9738 133.1716 470.381 Tm (i)Tj /F8 1 Tf 9.9626 0 0 9.9626 138.3874 472.7054 Tm (:)Tj /F6 1 Tf .552 0 TD .278 Tc (R!)Tj /F13 1 Tf 2.4014 0 TD 0 Tc (R)Tj /F5 1 Tf .9674 0 TD [(gives)-256(the)]TJ /F1 1 Tf 3.7956 0 TD [(singleton)-251.4(ener)-8.6(gy)]TJ /F5 1 Tf 6.9083 0 TD [(capt)-7.6(uring)-252.5(the)-251.5(interna)-8.1(l)-248.2(energy)-255.8(of)-249(a)-245.5(rotame)-8.5(r)-246.7(a)0(t)-249(posi)-7(tion)-247.6(i)-248.2(plus)-251.7(the)]TJ -15.814 -1.2007 TD [(energy)-341.2(between)-342.5(the)-336.9(rotame)-8.6(r)-332(and)-338(the)-336.9(backbone)-341.5(struct)-8.6(ure)-335.3(and)-332.3(side)-8.8(-chains)-337.4(at)-334.3(nonex)-8.1(ible)-340.4(positions.)]TJ /F6 1 Tf 7.9702 0 0 7.9702 117.5811 450.0849 Tm ()Tj /F12 1 Tf 9.9626 0 0 9.9626 126.5385 448.781 Tm (/)Tj /F5 1 Tf 6.9738 0 0 6.9738 133.1716 446.4566 Tm (i)Tj /F1 1 Tf .2845 0 TD ()Tj /F5 1 Tf .4959 0 TD (j)Tj /F8 1 Tf 9.9626 0 0 9.9626 143.8866 448.781 Tm (:)Tj /F6 1 Tf .5463 0 TD (R)Tj /F7 1 Tf 1.0129 0 TD ()Tj /F6 1 Tf .717 0 TD .2837 Tc (R!)Tj /F13 1 Tf 2.4071 0 TD 0 Tc (R)Tj /F5 1 Tf 1.0528 0 TD [(gives)-335.7(the)]TJ /F1 1 Tf 3.9606 0 TD [(pairw)-8.6(ise)-338.1(energy)]TJ /F5 1 Tf 6.8059 0 TD [(between)-342.5(a)-330.8(p)0(a)-7.2(i)0(r)-329.8(o)0(f)-334.3(rota)-7(mers)-341.2(at)-334.3(a)-330.8(pair)-337.1(of)-334.3(posi)-7(tions)-334.9(i)]TJ /F1 1 Tf 20.8331 0 TD (,)Tj /F5 1 Tf .5804 0 TD (j.)Tj /F1 1 Tf -41.5581 -1.7982 TD [(We)-267.6(use)]TJ /F6 1 Tf 3.2664 0 TD (A)Tj /F7 1 Tf .956 0 TD (=)Tj /F6 1 Tf .7227 0 TD (f)Tj /F1 1 Tf .5008 0 TD [(A)-166.8(C)]TJ /F8 1 Tf 2.5551 0 TD .1682 Tc (...)Tj /F1 1 Tf 1.3145 0 TD .1678 Tc (Y)Tj /F6 1 Tf 1.2235 0 TD 0 Tc (g)Tj /F1 1 Tf .7625 0 TD [(for)-268(the)-268.6(set)-269.8(of)-271(amino)-268(aci)-8.6(ds)-264.5(and)]TJ /F6 1 Tf 12.2461 0 TD (R)Tj /F1 1 Tf 1.1097 0 TD [(for)-268(the)-268.6(set)-269.8(of)-271(rotamers)-271.5(\(from)-275(a)-264.3(rotam)-8.2(er)-267.1(library)]TJ -24.6572 -1.2007 TD [(and)-334.1(the)-331.2(input)-328(stru)-9(cture\).)-333.9(We)-330.2(subsc)-8(ript)-329.2(seque)-8.6(nces)-332.2(with)-336.9(bracket)-9.7(s)-326.3(and)-334.1(use)-329.6(the)-331.2(nota)-7.6(tion)]TJ /F5 1 Tf 34.6611 0 TD (X)Tj /F1 1 Tf .6146 0 TD ([)Tj /F5 1 Tf .3301 0 TD (i)Tj /F1 1 Tf .2845 0 TD (..)Tj /F5 1 Tf .5008 0 TD (j)Tj /F1 1 Tf .2845 0 TD [(])-327.1(t)0(o)-328.7(indicate)-338.4(the)]TJ -36.6756 -1.2007 TD [(substring)-261.4(of)]TJ /F5 1 Tf 5.0134 0 TD (X)Tj /F1 1 Tf .865 0 TD [(from)-255.2(posi)-7(tion)]TJ /F5 1 Tf 5.6905 0 TD (i)Tj /F1 1 Tf .5349 0 TD (to)Tj /F5 1 Tf 1.03 0 TD (j)Tj /F1 1 Tf .2845 0 TD [(,)-250.8(inclusive.)-259.3(We)-256.2(wi)-8.2(ll)-251.7(use)-255.7(function)]TJ /F5 1 Tf 13.2931 0 TD (a)Tj /F8 1 Tf .7739 0 TD (:)Tj /F6 1 Tf .552 0 TD .2792 Tc (R!A)Tj /F1 1 Tf 3.4485 0 TD 0 Tc [(to)-254.7(obtain)-256.6(the)-251.5(amino)-262.3(acid)-254.1(type)]TJ -31.4858 -1.2007 TD [(of)-310.8(a)-315.5(give)-7.6(n)-308.1(rot)-7(amer.)-319.8(While)-315.3(our)-317.2(impleme)-10.1(ntation)-317(is)-312.8(modu)-6.6(lar)-316.1(and)-317.1(can)-313.2(suppor)-7.7(t)-310.8(a)-315.5(variety)-318(of)-316.5(epitope)-321.7(scores)-319.8(and)]TJ T* [(energy)-340.2(functi)-8.2(ons,)-333.9(we)-337.3(now)-336.3(sum)-7(marize)-336.9(thos)-7(e)-332.6(w)0(e)-337.3(use)-335.3(for)-336.3(the)-336.9(resu)-8(lts.)]TJ /F2 1 Tf 1.0015 -1.7982 TD [(Epitope)-242.6(score)-10.4(.)]TJ /F1 1 Tf 6.2994 0 TD [(Our)-241.5(epitope)-242.1(scor)-8(e)-235.9(i)0(s)-238.8(the)-240.2(n)-6.5(umber)-238.7(of)-242.5(the)-240.2(eigh)-7.6(t)-236.8(most)-238.2(com)-7.6(mon)-239.1(HLA)-10(-DR)-240.5(alleles)-247.8([represent)-11.5(ing)]TJ -7.301 -1.2007 TD [(a)-372.4(majority)-374.5(of)-373.4(human)-373.3(popul)-6.6(ations)-377.3(worldwid)-10.1(e)-366.7(\(Sout)-7.8(hwood)-371.9(et)-376(al.,)-371(1998\)])-372.7(predict)-10.7(ed)-373.2(by)-365.7(ProP)-9.2(red)-370.3(\(Sin)-7(gh)-365.7(and)]TJ T* [(Raghava)-9.7(,)-484.1(2001\))-489.5(to)-488(recognize)-491.1(a)-486.2(give)-7.6(n)-484.5(9-mer)-491.1(peptide)-492.4(at)-484.1(a)-486.3(5)0(%)-488(threshol)-10.9(d.)-484.8(If)-483.5(desired)-9.2(,)-484.1(a)-486.2()48.5(persona)-9.1(lized)41.3()]TJ T* [(therape)-9.7(utic)-397.3(could)-395.3(be)-396(designed)-400.6(by)-394.2(focusing)-400.8(on)-394.2(a)-389.5(partic)-10(ular)-396.5(set)-395(of)-390.5(allel)-10(es.)-391.8(ProPre)-8.7(d)-393.4(i)0(s)-392.4(a)0(n)-396(extensio)-10.7(n)-387.7(o)0(f)-396.2(the)]TJ 0 -1.195 TD [(TEPITO)-9.1(PE)-319.2()54.2(pock)-7.6(et)-319.1(prole)43.9()-315.7(method)-319.9(\(Sturni)-8.3(olo)-312.3(et)-319.1(al.,)-314.1(1999)-8.7(\),)-310.4(lea)-8.6(rning)-315.8(posi)-7(tion-speci)-11.2(c)-315.5(amino)-319.2(acid)-316.7(scor)-8(es)]TJ 0 -1.2007 TD [(from)-352(experiment)-12.6(ally)-346.1(measur)-9.1(ed)-350.4(binding)-352.3(afnities)-351.1(for)-347.7(indi)-8.6(vidual)-347.6(amino)-353.3(acid)-350.8(types)-351(at)-347.5(indivi)-7.2(dual)-349(pockets)-354.3(of)]TJ T* [(the)-297.1(MHC)-297.4(II)-295.7(binding)-295.4(groove)-298.6(\(Fig)-7(.)-290.6(1A\).)-298.8(Given)-296.8(a)-292.8(9-m)-7.8(er,)-295.9(the)-291.4(po)-7.2(sition-sp)-8.1(ecic)-295.7(weight)-10.1(s)-292.2(for)-296.5(its)-293.5(amino)-302.1(acids)-295.9(are)]TJ T* [(summe)-8.1(d,)-297.1(and)-305.7(the)-302.7(total)-304.1(is)-295.7(com)-7.6(pared)-305.3(to)-300.2(a)-298.5(threshol)-10.9(d)-296.7(t)0(o)-300.2(predict)-306.6(whe)-8(ther)-299.8(or)-305.1(not)-301(the)-297.1(g)-6.5(iven)-297.8(pept)-7.6(ide)-302.7(is)-301.4(in)-300.2(a)-298.5(given)]TJ T* [(percent)-9.7(ile)-254.3(of)-259.6(the)-257.2(best-recogn)-10.3(ize)-8.6(d)-251.2(pept)-7.6(ides.)-259.6(The)-254.3(amino)-262.3(acid)-259.8(in)-254.7(the)-257.2(rst)-258.6(pocket)-261.3(is)-255.9(terme)-10(d)-251.2(the)-257.2(P1)-256.8(anchor)-266.2(for)-256.6(its)]TJ T* [(signica)-9.9(nt)-328.6(cont)-7.6(ribution)-335(to)-328.7(binding.)-335.6(ProPre)-8.7(d)-325.1(has)-335.3(been)-331(succe)-10.4(ssfully)-333.9(emp)-7.6(loyed)-332.7(in)-328.7(a)-332.6(number)-336.2(of)-327.9(exper)-9.4(imental)]TJ T* [(studies)-305.2(\(e.g.,)-303.1(Must)-9(afa)-303.7(and)-300(Shaban,)-309.3(2006;)-302.5(Dinglasan)-311.3(et)-296.3(al.,)-302.7(2007)-8.7(;)-299.4(Klyushn)-7.5(enkova)-304.1(et)-302(al.,)-302.7(2007\))-301.7(and)-305.7(was)-299.4(o)-6.5(n)0(e)]TJ T* [(of)-339.2(the)-342.6(best)-338.8(predict)-10.7(ors)-341.2(in)-334.3(a)-344(recent)-344.7(independe)-9.3(nt)-340(assessment)-348.4(\(Wa)-8.6(ng)-337.3(et)-341.8(al.,)-336.9(2008)-8.7(\),)-338.9(achieving)-347.8(an)-339.1(average)-344.5(0.73)]TJ 0 -1.195 TD [(area)-266.5(under)-269.3(the)-268.6(curve)-265.4(in)-266.1(epitope)-270.5(predict)-10.7(ion.)-267.2(In)-259.6(o)-6.5(u)0(r)-259.6(earli)-9.2(er)-267.1(work,)-265.4(we)-269(found)-267.6(its)-265.1(predictio)-9.3(ns)-264.5(to)-266.1(have)-268.4(a)-264.3(strikingly)]TJ 0 -1.2007 TD [(good)-270.5(correspo)-9.1(ndence)-277.4(with)-268.6(a)-270(previous)-8.1(ly)-266.1(publishe)-8.9(d)-268.2(ELISP)-9.5(OT)-267(assa)-9(y)-262.5(\(Par)-8(ker)-267.8(et)-273.5(al.,)-268.6(2011b\))-6.6(,)-267.8(and)-265.9(used)-273.5(it,)-269.2(along)]TJ T* [(with)-336.9(conse)-8.6(rvation)-339(analysi)-9.9(s,)-332.4(to)-334.3(optim)-7.2(ize)-333(a)-338.3(set)-338.1(of)-333.6(mutation)-8.3(s)-332(for)-336.3(a)]TJ /F12 1 Tf 26.3643 0 TD (b)Tj /F1 1 Tf .882 0 TD [(lac)-8.6(tamase)-341.8(\(Osipovitch)-344.2(et)-336.1(al.,)-336.9(2012\).)]TJ /F2 1 Tf -26.2448 -1.7982 TD [(Molecul)-10.5(ar)-452.9(mec)-8.6(hanics)-458.3(energy)-464.4(function.)]TJ /F1 1 Tf 17.396 0 TD [(We)-438.3(as)23.9(se)18.3(ss)-436.4(si)17.3(ng)21.2(l)13.5(e)0(t)16.7(o)0(n)-434(a)0(n)19.5(d)-444.6(pa)19.4(i)13.5(r)0(w)15.3(i)13.5(se)-437(en)19.4(er)17.5(gi)24.2(es)-437(ac)17.7(co)19.4(rd)19.3(i)13.5(n)0(g)-434(t)0(o)-436.8(t)13.5(he)]TJ -18.3975 -1.2007 TD [(AM)21(BE)16.7(R)-278.6(f)0(o)19.3(r)14.3(ce)-272.6()11.4(e)0(l)22.4(d)-279.6(as)-266.3(i)13.5(m)0(p)17.7(l)0(e)22.4(m)0(e)15.9(n)0(t)18.5(e)0(d)-265.1(i)0(n)-266.1(t)13.5(he)-270.8(O)12.4(s)0(p)20(r)0(e)17.5(y)-273.9(so)20(ft)16.5(w)12.4(a)0(r)17.5(e)-275.7(pa)19.4(ck)19.5(ag)19.5(e)-275.7(f)0(o)19.3(r)-275.9(pr)19.3(ot)18.5(ei)22.4(n)-279.6(r)14.3(ed)19.4(es)18.3(ig)18.5(n)-273.9(\()0(C)20.2(h)0(e)19.4(n)-279.6(et)-262.2(al)16.7(.,)-262.5(20)21.2(09)15.5(\))14.3(.)]TJ T* [(In)-339.2(pa)19.4(rt)16.5(i)13.5(c)0(u)19.4(l)0(a)16.7(r)14.3(,)-353.2(w)12.4(e)-355.4(u)0(s)20(e)-349.7(th)18.5(e)-349.7(v)0(a)19.4(n)-353.6(de)19.4(r)-349.9(W)0(a)16.9(a)0(l)22.4(s)-349.1(an)13.8(d)-347.9(e)0(l)16.7(e)14.5(ct)16.7(ro)19.3(t)13.5(a)0(t)16.7(i)0(c)22.4(s)-354.8(fo)19.3(r)14.3(c)0(e)17.7(s)-354.8(a)14.5(s)-354.8(w)12.4(e)0(l)16.7(l)-350.7(as)-340.2(an)-344.7(i)13.5(m)0(p)17.7(l)13.5(ic)16.7(it)-337.1(so)14.4(l)13.5(v)0(a)19.4(t)0(i)21.4(o)0(n)-343(f)0(a)17.5(c)0(t)22.4(o)0(r)-339.3(a)0(n)19.5(d)]TJ T* [(re)17.5(si)23(du)21.2(e)-355.4(r)14.3(ef)17.5(er)17.5(en)19.4(ce)-340.8(en)19.4(er)17.5(gi)18.5(es)-340.2(as)-340.2(in)18.5(te)16.7(nd)21.2(ed)-339.1(fo)19.3(r)-349.9(s)0(t)17.3(a)0(n)19.4(d)0(a)19.4(r)0(d)-339.2(p)0(r)19.3(o)0(t)18.5(e)0(i)22.4(n)-353.6(re)17.5(de)19.4(si)23(gn)-343(\(a)23.2(s)-354.8(o)0(p)21.2(p)0(o)21.2(s)0(e)18.3(d)-353.6(t)13.5(o)-353.6(ac)17.7(t)13.5(i)0(v)18.5(e)-349.7(si)17.3(te)-341.8(re)17.5(de)19.4(si)23(gn)-343(fo)19.3(r)]TJ T* [(ch)19.4(an)19.4(ge)-213.9(of)-214.1(su)20(bs)20(t)13.5(r)0(a)17.5(t)0(e)-216.6(s)0(p)20(e)0(c)17.7(i)13.5()11.4(c)0(i)16.7(t)0(y)18.5(\))14.3(.)-222.3(W)0(e)-216.4(d)0(i)18.5(s)0(c)18.3(a)0(r)17.5(d)-222.7(r)14.3(o)0(t)18.5(a)0(m)15.9(e)0(r)23.2(s)0(,)-212.9(a)0(n)19.4(d)-228.4(t)13.5(h)0(u)21.2(s)-223.9(al)16.7(l)-219.8(c)0(o)19.4(n)0(f)19.3(o)0(r)19.3(m)0(a)15.9(t)13.5(io)18.5(ns)-213.3(co)19.4(nt)18.5(ai)22.4(ni)18.5(ng)-212.1(th)18.5(em)21.6(,)-222.3(i)0(f)-216.8(t)13.5(he)19.4(y)-222.7(h)0(a)19.4(v)0(e)]TJ T* [(si)23(gn)15.5(i)13.5()11.4(ca)17.7(nt)-317.3(ov)21.2(er)23.2(la)16.7(p)-325.1(o)0(f)-310.8(v)0(a)19.4(n)-325.1(de)19.4(r)-321.4(W)0(a)16.9(a)0(l)22.4(s)-326.3(ra)17.5(di)24.2(i)-322.2(o)0(r)-316.5(o)0(t)24.2(h)0(e)19.4(r)0(w)15.3(i)13.5(se)-317.5(ex)19.4(ce)17.7(pt)24.2(io)18.5(na)19.4(ll)21.4(y)-325.1(h)0(i)18.5(g)0(h)-308.8(i)0(n)18.5(t)0(r)22.2(a)0(-)-318.3(o)0(r)-310.8(i)0(n)18.5(t)13.5(er)17.5(-r)23(ot)18.5(am)15.9(er)-312.6(en)19.4(er)17.5(gi)24.2(es)18.3(.)]TJ /F5 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TD (to)Tj /F5 1 Tf 1.0243 0 TD (f)Tj /F14 1 Tf 7.4718 0 0 6.641 440.107 582.2927 Tm (e)Tj /F1 1 Tf 9.9626 0 0 9.9626 442.9983 583.9935 Tm (\()Tj /F5 1 Tf .3357 0 TD (A)Tj /F6 1 Tf 6.9738 0 0 6.9738 452.466 587.6219 Tm (0)Tj /F1 1 Tf 9.9626 0 0 9.9626 454.8471 583.9935 Tm [(\),)-247.8(and)-243.1(repe)-8.6(at)]TJ -38.2177 -1.2007 TD [(un)-7.2(til)-340.6(there)-342.2(is)-341.2(n)-6.5(o)-336.5(solu)-7(tion)-338.6(mee)-9.4(ting)-344.3(the)-342.6(smaller)-345.5(epitope)-350.2(constra)-9.1(int.)-338.2(Clear)-11.2(ly,)-340.4(each)-344.2(iden)-7.6(tied)-346.1(design)-346.1(is)-341.2(Pareto)]TJ T* [(op)-7.2(timal,)-353.5(and)-351.2(all)-356.7(Pareto-opti)-12(mal)-351.8(designs)-353.7(are)-355(iden)-7.6(tied.)-352.1(In)-350.6(addi)-7.6(tion,)-350.4(the)-354(appro)-7.6(ach)-353(is)-352.6(efcient)-359.6(in)-351.4(an)-350.4(outpu)-6.6(t-)]TJ T* [(sensi)-10.7(tive)-334.7(fashion,)-343.5(only)-335.9(requiring)]TJ /F5 1 Tf 13.5264 0 TD (D)Tj /F1 1 Tf 1.0528 0 TD 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[(.)-262.2(Den)-8(e)-264.3(pairwise)-272.7(binary)-267.2(variabl)-10.7(e)]TJ /F5 1 Tf 13.4525 0 TD (p)Tj 7.4718 0 0 6.641 454.5637 486.6519 Tm (i)Tj /F1 1 Tf .2807 0 TD (,)Tj /F5 1 Tf .2504 0 TD (j)Tj /F1 1 Tf .2807 0 TD (,)Tj /F5 1 Tf .2504 0 TD (r)Tj /F1 1 Tf .387 0 TD (,)Tj /F5 1 Tf .2504 0 TD (t)Tj /F1 1 Tf 9.9626 0 0 9.9626 469.3605 488.3526 Tm [(,)-262.2(derived)]TJ -39.6745 -1.2007 TD (from)Tj /F5 1 Tf 2.1852 0 TD (s)Tj 7.4718 0 0 6.641 99.6661 474.7463 Tm (i)Tj /F1 1 Tf .2883 0 TD (,)Tj /F5 1 Tf .2504 0 TD (r)Tj /F1 1 Tf 9.9626 0 0 9.9626 108.8504 476.3904 Tm (and)Tj /F5 1 Tf 1.6787 0 TD (s)Tj 7.4718 0 0 6.641 129.3732 474.7463 Tm (j)Tj /F1 1 Tf .2883 0 TD (,)Tj /F5 1 Tf .2504 0 TD (t)Tj /F1 1 Tf 9.9626 0 0 9.9626 135.496 476.3904 Tm [(,)-228(t)0(o)-231.9(indicate)-236(whethe)-9.1(r)-230.4(o)0(r)-231.1(not)-227(the)-234.5(rotam)-8.2(ers)-229.2(at)-233.7(positions)]TJ /F5 1 Tf 20.964 0 TD (i)Tj /F1 1 Tf .5121 0 TD (and)Tj /F5 1 Tf 1.6787 0 TD (j)Tj /F1 1 Tf .5122 0 TD 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[(sweep)-280(for)-268(the)-274.3(epitope)-281.9(score)-272.3(wi)-8.2(thin)-270.3(the)-274.3(pept)-7.6(ide)-268.6(whi)-9(le)-267.8(avoi)-7.6(ding)-273.3(the)-274.3(introdu)-7.1(ction)-272.9(of)-271(addi)-7.6(tional)-276.4(epitope)-8.7(s)-269.4(i)0(n)-271.8(the)]TJ T* [()48.5(anking)-245.2(regions)41.1()-236.1(up-)-237.6(and)-237.4(down)-7(stream)-239.5(from)-243.8(that)-238(peptide)-242.1(\(i.e.,)-243.3(9-mers)-242.6(spanning)-239.5(p)-6.5(art)-236.4(of)-236.8(the)-240.2(peptide)-242.1(and)-237.4(part)]TJ T* [(of)-333.6(the)-336.9(protei)-8.2(n)-330.8(N)0(-)-337.5(o)0(r)-333.6(C-te)-8.6(rminal)-336.1(to)-334.3(it)-7.1(\).)]TJ 1.0015 -1.195 TD [(Let)-268.4(the)-274.3(peptide)-276.2(of)-271(interest)-277.2(span)-267.8(from)-272.3(residue)]TJ /F5 1 Tf 18.1699 0 TD (p)Tj 7.4718 0 0 6.641 303.5905 606.2172 Tm (l)Tj /F1 1 Tf 9.9626 0 0 9.9626 308.4093 607.918 Tm [(to)-266.1(residue)]TJ /F5 1 Tf 4.2167 0 TD (p)Tj 7.4718 0 0 6.641 355.4078 606.2172 Tm (h)Tj /F7 1 Tf 9.9626 0 0 9.9626 362.4944 607.918 Tm ()Tj /F5 1 Tf .8877 0 TD (p)Tj 7.4718 0 0 6.641 376.3275 606.2172 Tm (l)Tj /F7 1 Tf 9.9626 0 0 9.9626 381.77 607.918 Tm (+)Tj /F1 1 Tf .882 0 TD [(9)-273.9(\(so)]TJ /F5 1 Tf 2.2592 0 TD (M)Tj /F6 1 Tf 1.1552 0 TD .2771 Tc (f)Tj /F5 1 Tf 1.5478 0 TD 0 Tc (p)Tj 6.9738 0 0 6.9738 444.9825 606.3872 Tm (l)Tj /F1 1 Tf 9.9626 0 0 9.9626 447.4771 607.918 Tm ()Tj /F8 1 Tf .6658 0 TD .1682 Tc (...)Tj /F1 1 Tf 1.3145 0 TD 0 Tc ()Tj /F5 1 Tf .5008 0 TD (p)Tj 6.9738 0 0 6.9738 477.1841 606.3872 Tm (h)Tj /F6 1 Tf 9.9626 0 0 9.9626 481.1526 607.918 Tm (g)Tj /F1 1 Tf .5008 0 TD [(\).)-270.6(Th)-7(en)-265.1(ther)-9.6(e)]TJ -37.9958 -1.2007 TD [(are)-650.9(three)-655.2(sets)-653(of)-646.5(start)-8.6(ing)-648.1(positions)-654.9(for)-649.3(the)-649.9(9-m)-7.8(ers)-650.3(to)-647.3(be)-652(assessed)-10.5(:)-646.6(N-term)-9.2(inal)-653.4(anking)-652.1(positio)-9.1(ns)]TJ /F5 1 Tf T* (P)Tj 6.9738 0 0 6.9738 113.726 582.4628 Tm (l)Tj /F7 1 Tf 9.9626 0 0 9.9626 117.8645 583.9935 Tm (=)Tj /F6 1 Tf .717 0 TD (f)Tj /F1 1 Tf .5008 0 TD (max)Tj /F6 1 Tf 1.7356 0 TD (f)Tj /F1 1 Tf .5008 0 TD (1)Tj /F5 1 Tf 1.0015 0 TD (p)Tj 6.9738 0 0 6.9738 167.244 582.4628 Tm (l)Tj /F7 1 Tf 9.9626 0 0 9.9626 171.3826 583.9935 Tm (-)Tj /F1 1 Tf .717 0 TD (8)Tj /F6 1 Tf .5008 0 TD (g)Tj /F1 1 Tf .5008 0 TD ()Tj /F8 1 Tf .6658 0 TD .1682 Tc (...)Tj /F1 1 Tf 1.3145 0 TD 0 Tc [()-338.5(max)]TJ /F6 1 Tf 2.4014 0 TD (f)Tj /F1 1 Tf .5008 0 TD (1)Tj /F5 1 Tf 1.0015 0 TD (p)Tj 6.9738 0 0 6.9738 252.1133 582.4628 Tm (l)Tj /F7 1 Tf 9.9626 0 0 9.9626 256.2519 583.9935 Tm (-)Tj /F1 1 Tf .717 0 TD (1)Tj /F6 1 Tf .5008 0 TD (gg)Tj /F1 1 Tf 1.0015 0 TD [(,)-455.6(core)-458.2(positions)]TJ /F5 1 Tf 6.9652 0 TD (P)Tj 6.9738 0 0 6.9738 353.8771 582.4628 Tm (c)Tj /F7 1 Tf 9.9626 0 0 9.9626 359.1495 583.9935 Tm (=)Tj /F6 1 Tf .7227 0 TD (f)Tj /F5 1 Tf .5008 0 TD (p)Tj 6.9738 0 0 6.9738 376.3275 582.4628 Tm (l)Tj /F1 1 Tf 9.9626 0 0 9.9626 378.7652 583.9935 Tm ()Tj /F8 1 Tf .6715 0 TD .1625 Tc [(..)-5.7(.)]TJ /F1 1 Tf 1.3088 0 TD 0 Tc ()Tj /F5 1 Tf .5008 0 TD (p)Tj 6.9738 0 0 6.9738 408.4723 582.4628 Tm (h)Tj /F7 1 Tf 9.9626 0 0 9.9626 414.1416 583.9935 Tm (-)Tj /F1 1 Tf .7227 0 TD (8)Tj /F6 1 Tf .5008 0 TD (g)Tj /F1 1 Tf .5008 0 TD [(,)-449.9(and)-459.3(C-termina)-11.1(l)-453.1(anking)]TJ -32.493 -1.2007 TD (positions)Tj /F5 1 Tf 3.9663 0 TD (P)Tj 6.9738 0 0 6.9738 153.2409 570.5574 Tm (h)Tj /F7 1 Tf 9.9626 0 0 9.9626 158.9102 572.0314 Tm (=)Tj /F6 1 Tf .717 0 TD (f)Tj /F5 1 Tf .5008 0 TD (p)Tj 6.9738 0 0 6.9738 176.0314 570.5574 Tm (h)Tj /F7 1 Tf 9.9626 0 0 9.9626 181.7007 572.0314 Tm (-)Tj /F1 1 Tf .717 0 TD (7)Tj /F8 1 Tf 1.1723 0 TD .1682 Tc (...)Tj /F1 1 Tf 1.3145 0 TD 0 Tc ()Tj /F5 1 Tf .5008 0 TD (p)Tj 6.9738 0 0 6.9738 223.5968 570.5574 Tm (h)Tj /F6 1 Tf 9.9626 0 0 9.9626 227.5653 572.0314 Tm (g)Tj /F1 1 Tf .5008 0 TD [(.)-347.5(W)0(e)-347.3(replace)-353(Equat)-8.2(ion)-346.5(4)-342.2(with)-348.3(a)-344(scor)-8(e)-344(for)-347.7(just)-345.5(the)-348.3(9-m)-7.8(ers)-343(in)-345.7(the)-348.3(pept)-7.6(ide)-348.3(of)]TJ -12.542 -1.2007 TD [(interest)-339.8(\(i.)-6.6(e.,)-333.4(starting)-338(at)-336.1(the)-336.9(core)-338.7(posi)-7(tions\):)]TJ /F11 1 Tf 17.8 -1.1723 TD (X)Tj /F5 1 Tf 6.9738 0 0 6.9738 281.3102 528.3211 Tm (i)Tj /F6 1 Tf .2764 0 TD (2)Tj /F5 1 Tf .6585 0 TD (P)Tj 4.9813 0 0 4.9813 292.1385 527.3007 Tm (c)Tj /F1 1 Tf 6.9738 0 0 6.9738 294.8597 528.3211 Tm ()Tj /F5 1 Tf .504 0 TD (X)Tj 9.9626 0 0 9.9626 304.611 538.9794 Tm (w)Tj 6.9738 0 0 6.9738 311.244 537.5054 Tm (i)Tj /F1 1 Tf .2845 0 TD ()Tj /F5 1 Tf .4959 0 TD (X)Tj /F6 1 Tf 9.9626 0 0 9.9626 323.9999 538.9794 Tm ()Tj /F5 1 Tf .4951 0 TD (f)Tj /F9 1 Tf 6.9738 0 0 6.9738 331.7101 537.5054 Tm ()Tj /F10 1 Tf 9.9626 0 0 9.9626 334.9984 538.9794 Tm (\()Tj /F5 1 Tf .3244 0 TD (X)Tj /F10 1 Tf .6544 0 TD (\))Tj /F16 1 Tf .3244 0 TD (p)Tj /F5 1 Tf 1.0015 0 TD (E)Tj /F10 1 Tf 16.4229 0 TD (\()Tj /F1 1 Tf .3187 0 TD .0065 Tc (10)Tj /F10 1 Tf 1.0072 0 TD 0 Tc (\))Tj /F1 1 Tf -42.8783 -2.9249 TD [(and)-282.9(initializ)-9.9(e)]TJ /F5 1 Tf 5.5426 0 TD (E)Tj /F1 1 Tf .8934 0 TD [(wi)-8.2(th)-277.4(a)-281.4(wild-ty)-8.1(pe)-276.5(total)-287(that)-283.5(is)-278.6(likewis)-9.1(e)-281.4(restricted.)-288.6(We)-284.7(also)-281.9(add)-282.9(anking)-282.2(region)-284.2(const)-9.5(raints)-282.5(to)]TJ -6.436 -1.195 TD [(prevent)-338(int)-7.8(roducing)-337(new)-338.1(epitope)-8.7(s:)]TJ /F6 1 Tf 12.468 -1.9234 TD (8)Tj /F5 1 Tf .552 0 TD (i)Tj /F6 1 Tf .5577 0 TD (2)Tj /F5 1 Tf .9389 0 TD (P)Tj 6.9738 0 0 6.9738 258.3495 477.2975 Tm (l)Tj /F6 1 Tf 9.9626 0 0 9.9626 262.9984 478.7715 Tm ([)Tj /F5 1 Tf .882 0 TD (P)Tj 6.9738 0 0 6.9738 277.9086 477.2975 Tm (h)Tj /F6 1 Tf 9.9626 0 0 9.9626 284.655 478.7715 Tm (8)Tj /F5 1 Tf .552 0 TD (X)Tj /F8 1 Tf 1.2121 0 TD (:)Tj /F5 1 Tf .8308 0 TD (w)Tj 6.9738 0 0 6.9738 317.1401 477.2975 Tm (i)Tj /F1 1 Tf .2845 0 TD ()Tj /F5 1 Tf .4959 0 TD (X)Tj /F6 1 Tf 9.9626 0 0 9.9626 329.896 478.7715 Tm ()Tj /F5 1 Tf .4951 0 TD (f)Tj /F9 1 Tf 6.9738 0 0 6.9738 337.6062 477.2975 Tm ()Tj /F10 1 Tf 9.9626 0 0 9.9626 340.8944 478.7715 Tm (\()Tj /F5 1 Tf .3244 0 TD (X)Tj /F10 1 Tf .6544 0 TD (\))Tj /F16 1 Tf .3244 0 TD (p)Tj /F5 1 Tf 1.0015 0 TD (f)Tj /F9 1 Tf 6.9738 0 0 6.9738 366.633 477.2975 Tm ()Tj /F10 1 Tf 9.9626 0 0 9.9626 369.9211 478.7715 Tm (\()Tj /F5 1 Tf .3244 0 TD (A)Tj /F10 1 Tf .6146 0 TD ([)Tj /F5 1 Tf .3244 0 TD (i)Tj /F9 1 Tf .2788 0 TD (::)Tj /F5 1 Tf .5463 0 TD (i)Tj /F7 1 Tf .4439 0 TD (+)Tj /F1 1 Tf .7227 0 TD (8)Tj /F10 1 Tf .5008 0 TD [(]\))-10822.5(\()]TJ /F1 1 Tf 11.7851 0 TD .0065 Tc (11)Tj /F10 1 Tf 1.0072 0 TD 0 Tc (\))Tj /F5 1 Tf 10.959 0 0 10.959 107.6031 455.0739 Tm [(2.2.)-496.9(Preprocessing)-328.4(lters)]TJ /F1 1 Tf 9.9626 0 0 9.9626 117.5811 437.1589 Tm [(In)-384.8(practice,)-396.7(it)-382.6(is)-386.7(oft)-7(en)-384.6(help)-7.6(ful)-382.6(to)-391.3(prune)-388.8(the)-388.1(search)-394.4(space)-391.6(in)-385.6(order)-390.8(to)-385.6(focus)-390(the)-388.1(combina)-9.5(torial)-392.2(space)-391.6(of)]TJ -1.0015 -1.2007 TD [(designs,)-422.4(employi)-10.5(ng)-411.3(addi)-7.6(tional)-418.7(backgr)-10.1(ound)-418.5(knowled)-8.1(ge)-418.7(to)-414(limit)-422.4(the)-416.6(designs)-422(to)-414(be)-418.7(consider)-9.9(ed,)-419.1(as)-414.2(well)-424(as)]TJ T* [(elimina)-9.3(ting)-281.7(regions)-280.5(of)-282.3(the)-280(space)-283.5(guara)-9.4(nteed)-283.3(to)-277.4(be)-276.5(subopt)-8.5(imal.)-281.7(Our)-281.3(imple)-9(mentatio)-10.1(n)-273.9(inco)-7.6(rporates)-285(two)-282.1(lters.)]TJ /F2 1 Tf 1.0015 -1.7982 TD [(Homolo)-7.9(gy)-525.1(lters.)]TJ /F1 1 Tf 8.1546 0 TD [(Natural)-532.5(variation)-532.8(provides)-531.7(insight)-9.1(s)-525.5(into)-526.4(mutation)-8.3(s)-525.5(likely)-526.8(to)-527.8(yield)-529(stable)-9.2(,)-523.9(active)]TJ -9.1561 -1.2007 TD [(structure)-9.7(s.)-434.8(We)-432.7(can)-432.7(restri)-11.3(ct)-432.9(the)-433.6(allowed)-439.5(mutation)-8.3(s)-428.7(t)0(o)-436.8(b)0(e)-430.1(consi)-9.6(dered)-436.2(at)-432.9(each)-435.2(positi)-8.4(on,)-428.7(based)-441.1(either)-436.8(on)-434(a)]TJ T* [(general)-254.4(subst)-9(itution)-249.7(matrix)-256.4(such)-250.7(as)-254.9(BLOSUM,)-257.5(or)-248.2(on)-251.9(a)-247.2(posi)-7(tion-speci)-11.3(c)-247.2(asse)-9(ssment)-254(of)-248.2(conse)-8.6(rvation)-253.6(within)-255.8(a)]TJ T* [(multipl)-8.5(e)-264.3(seque)-8.6(nce)-267.6(alignm)-9.7(ent)-268.6(\()-82.4(MSA)-7.4(\))-264.5(o)0(f)-271(homo)-6.6(logs)-268.8(to)-266.1(the)-268.6(target)-10(.)-262.1(F)0(o)-6.4(r)-264.5(BLOSU)-9.7(M,)-270.6(we)-269(elimina)-9.3(te)-267.8(an)-265.1(amino)-273.7(acid)]TJ T* [(\(and)-297(thereby)-303.9(all)-294.1(its)-293.5(rot)-7(amers\))-301.3(at)-290.6(a)-298.5(position)-300.1(if)-290.8(its)-299.2(BLOSU)-9.7(M62)-294.5(scor)-8(e)-292.8(vs.)-293.3(the)-297.1(wild-)-9.6(type)-292.1(amino)-302.1(acid)-299.6(exceeds)-303.9(a)]TJ T* [(specied)-293.5(threshold.)-290.9(For)-282.3(conse)-8.6(rvation,)-288.2(we)-286.1(likewise)-290.5(elimina)-9.3(te)-279.2(an)-287.8(amino)-285(aci)-8.6(d)-279.6(and)-282.9(its)-287.8(rotamers)-288.6(at)-284.9(a)-281.4(posi)-7(tion)-281.7(if)]TJ T* [(its)-242.3(freq)-8.8(uency)-246.4(in)-243.3(the)-245.8(MSA)-246.4(is)-244.5(below)-245.6(that)-243.7(in)-243.3(a)-247.2(specied)-247.9(backgr)-10.1(ound)-242.1(distri)-10.3(bution)-243.4(\()-88.1(McCaldon)-252.4(and)-243.1(Argos,)-250.3(1988\).)]TJ /F2 1 Tf 1.0015 -1.7982 TD [(Dead-end)-496.9(elimin)-10.9(ation.)]TJ /F1 1 Tf 10.1918 0 TD [(Th)-7(e)-486.3(d)-6.5(ead-end)-496.4(elimina)-9.3(tion)-492.3(\(DE)-8(E\))-492.7(criterion)-495(provi)-8.6(des)-494.7(a)-491.9(pruning)-493.8(techniq)-8.7(ue)-492.7(to)]TJ -11.1933 -1.2007 TD [(elimina)-9.3(te)-506.8(rotamers)-510.5(that)-511.1(are)-508.6(prova)-7.6(bly)-505.8(not)-505.8(part)-510.3(of)-504.3(the)-507.6(globa)-8.4(l)-504.3(minimum)-510.8(ener)-8.6(gy)-502.3(confo)-7.6(rmation)-513.2(\(GMEC)-10.5(\))]TJ T* [(\(Desmet)-306.8(et)-302(al.,)-302.7(1992\).)-302.1(DEE)-307.4(has)-301.2(been)-302.5(gener)-9.4(alized)-305.7(and)-300(extend)-10.9(ed)-299.2(in)-300.2(a)-298.5(numb)-6.6(er)-301.2(of)-299.4(powe)-8.8(rful)-300(ways)-305.9(\(e.g.,)-303.1(Lilien)]TJ T* [(et)-353.2(al.,)-348.3(2004;)-353.7(Geo)-8(rgiev)-351.8(et)-353.2(al.,)-354(2006;)-353.7(Chen)-351(et)-353.2(al.,)-354(2009\);)-350.7(we)-354.4(nd)-354.3(the)-348.3(simpl)-8.4(e)-349.7(Goldst)-9.5(ein)-348.3(DEE)-358.7(criterion)-358.4(to)-345.7(be)]TJ 0 -1.195 TD [(sufc)-8(ient)-448.5(for)-450.1(our)-453.8(current)-453.8(purpos)-7.7(es)-454.1(\(Goldste)-9.1(in,)-448.5(1994\).)-455.7(However,)-457.3(DEE)-455.4(is)-449.3(correct)-455.6(only)-449.7(for)-455.8(pruning)-453.9(with)]TJ 0 -1.2007 TD [(respect)-392.2(to)-379.9(the)-382.4(ov)-7.2(erall)-384.8(GME)-8(C;)-378.9(it)-382.6(do)-7.2(es)-380.1(not)-386.3(account)-389(for)-381.8(our)-385.5(epitope)-390(score)-386.1(constra)-9.2(int,)-383.8(which)-387.9(might)-388.4(require)]TJ T* [(making)-240.3(mor)-7.8(e)-235.9(dras)-8(tic)-237.2(mutation)-8.3(s)-235.3(and)-243.1(thus)-240.3(employ)-240.3(rot)-7(amers)-241.7(that)-243.7(would)-238.1(be)-242.3(pruned)-241.6(if)-239.6(relying)-242.2(exclusiv)-10.7(ely)-234.5(on)-240.5(the)]TJ T* [(GME)-8(C)-324.2(crite)-9.2(rion.)-326.8(To)-331.4(ensur)-8.8(e)-326.9(that)-329(we)-331.6(do)-325.9(not)-329.4(elim)-8.2(inate)-331.6(rotam)-8.2(ers)-325.9(cont)-7.6(ributing)-335(to)-323(Pa)-8.2(reto)-328.3(optim)-7.2(al)-324.7(desi)-8.8(gns,)-328.2(we)]TJ T* [(employ)-274.4(the)-274.3(common)-275.2(tec)-8.6(hnique)-270.9(o)-6.5(f)-270.2(performi)-8.7(ng)-269(DEE)-273.3(with)-274.3(resp)-8(ect)-270.4(to)-271.7(a)-270()48.5(buf)-7(fer)46.1()-270.2(energy)]TJ /F12 1 Tf 34.7749 0 TD (d)Tj /F1 1 Tf .5008 0 TD [(,)-267.8(such)-273.5(that)-272.1(rot)-7(amers)]TJ -35.2757 -1.2007 TD [(are)-349.3(pruned)-349.8(only)-347.2(if)-347.7(they)-343.3(p)-6.5(rovably)-347.6(do)-348.7(not)-346.5(participa)-11.1(te)-341.8(in)-345.7(any)-351.2(conform)-8.9(ation)-346.9(whos)-8.2(e)-344(energy)-351.6(is)-346.9(within)]TJ /F12 1 Tf 39.942 0 TD (d)Tj /F1 1 Tf .8479 0 TD [(of)-344.9(the)]TJ -40.7899 -1.2007 TD [(GME)-8(C.)-301.8(We)-313.2(do)-303.1(this)-311.4(DEE)-307.4(pruni)-8.6(ng)-303.1(before)-313.7(initiatin)-8.1(g)-302.4(the)-308.4(epitope)-316(sweep.)-308.8(If)-307.1(duri)-7.8(ng)-303.1(the)-308.4(sweep)-314.1(we)-308.8(nd)-308.8(that)-306.3(the)]TJ T* [(solution)-448.1(for)-438.7(a)-446.4(particula)-11.1(r)-440.9(epitope)-446.9(value)-442.6(has)-443.4(ener)-8.6(gy)-439.7(excee)-11(ding)-444(the)-439.3(GM)-7.4(EC)]TJ /F7 1 Tf 30.7005 0 TD (+)Tj /F12 1 Tf .717 0 TD (d)Tj /F1 1 Tf .5008 0 TD [(,)-444.3(w)0(e)-439.7(mus)-7(t)-441.7(decide)-445.2(either)-448.1(to)]TJ -31.9183 -1.195 TD [(terminate)-270.7(the)-268.6(sweep)-268.6(\(we)-266.1(do)-263.3(not)-266.8(care)-266.5(to)-266.1(produc)-8.3(e)-264.3(designs)-268.3(with)-268.6(energy)-266.2(so)-264.5(high\))-270.3(or)-259.6(to)-266.1(re-perfo)-11.9(rm)-263.1(DEE)-267.6(with)-268.6(an)]TJ 0 -1.2007 TD [(increas)-10.9(ed)]TJ /F12 1 Tf 4.1313 0 TD (d)Tj /F1 1 Tf .8365 0 TD [(and)-334.1(then)-337.7(re-optim)-9.5(ize)-338.7(for)-336.3(that)-334.7(epitope)-338.8(valu)-7.6(e)-332.6(and)-339.8(continue)-339.6(the)-336.9(sweep.)]TJ /F5 1 Tf 10.959 0 0 10.959 107.6031 123.9306 Tm [(2.3.)-496.9(Postprocessing)-330.7(energy)-331.4(minimization)]TJ /F1 1 Tf 9.9626 0 0 9.9626 117.5811 105.959 Tm 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[(PROT)-9.3(EIN)-336.5(DEIM)-9.7(MUNIZAT)-13.2(ION)-27359.7(157)]TJ ET endstream endobj 25 0 obj <> endobj 26 0 obj <>/ProcSet[/PDF/Text]/ExtGState<>>> endobj 27 0 obj <>stream /GS1 gs BT /F1 1 Tf 9.9626 0 0 9.9626 74.0976 715.4644 Tm 0 0 0 rg 0 Tc 0 Tw [(usin)-7(g)-410.5(the)-410.9(AM)-7.4(BER)-415.6(\(AMBER)-10.3(-f99sb\))-416.5(force)-415.4(eld)-410.8(\(H)-7.4(ornak)-411.6(et)-415.8(al.,)-410.9(2006\))-415.5(and)-413.8(the)-410.9(general)-9.7(ized)-413.4(Born)-413.8(solv)-7(ent)]TJ 0 -1.195 TD [(mode)-8.4(l.)-242.9(The)-242.9(backbo)-8.2(ne)-242.3(atoms)-246.4(\(N,)-241.1(C)]TJ /F12 1 Tf 13.7597 0 TD (a)Tj /F1 1 Tf .5008 0 TD [(,)-239.4(C)0(,)-244.9(and)-243.1(O\))-240.7(are)-246.8(held)-246.6(xed,)-243.4(as)-243.5(in)-243.3(the)-240.2(design)-249.3(target,)-243.7(and)-248.8(the)-240.2(side-ch)-9.1(ains)-247.8(are)]TJ -14.2605 -1.2007 TD [(allow)-9.4(ed)-333.4(to)-334.3(relax)-342.2(from)-334.9(their)-343.2(discrete)-338.8(rot)-7(americ)-336.9(sta)-8(tes.)]TJ 1.0015 -1.2007 TD [(Since)-436.2(a)-429.3(subopt)-8.5(imal)-435(design)-431.4(may)-434.4(relax)-433.2(to)-431.1(a)-429.3(confo)-7.6(rmation)-439.3(with)-433.6(a)-429.3(better)-436.7(energy)-436.9(than)-428.7(the)-433.6(one)-430.9(that)-437.2(was)]TJ -1.0015 -1.2007 TD [(ori)-7(ginally)-476.3(deemed)-480.1(optim)-7.2(al)-472.7(with)-479.1(rigid)-477.9(rotamers)-9.7(,)-472.7(w)0(e)-473.9(also)-475.4(consi)-9.6(der)-472.7(near)-8.6(-optimal)-476.9(desi)-8.8(gns.)-470.5(To)-479.3(do)-473.9(so,)-469.7(we)]TJ T* [(gener)-9.4(ate)-287.5(successi)-12.1(ve)-282.2(Pareto)-290.9(near-opt)-10.7(imal)-287(curves,)-290.5(each)-287.2(one)-288.6(Pareto)-290.9(optimal)-286.4(with)-291.3(respect)-289.8(to)-283.1(all)-288.4(designs)-291.1(except)]TJ T* [(thos)-7(e)-270(o)0(n)-269(the)-274.3(previous)-8.1(ly)-271.7(identi)-8.9(ed)-270.8(curves.)-273.5(Th)-7(is)-267.2(is)-272.9(done)-272.3(by)-269(addi)-7.6(ng)-269(constra)-9.1(ints)-271.5(in)-271.7(succe)-10.4(ssive)-272.5(rounds)-275.2(to)-271.8(ensure)]TJ T* 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[(\(G)-7.4(ainza)-239.6(et)-233.7(al.,)-240.2(2012\))-239.1(variants)-240.3(of)-236.8(DEE)-239.2(ensure)-238.9(that)-238(in)-237.6(the)-234.5(pre-proc)-9.9(essing)-239.1(stage,)-239.3(rot)-7(amers)-236(are)-241.1(elimina)-9.3(ted)-234.5(only)-239.1(if)]TJ T* [(they)-263.7(cannot)-261.3(participate)-267.6(in)-254.7(a)-252.9(desi)-8.8(gn)-251.9(that)-260.7(would)-260.9(be)-253.7(optim)-7.2(al)-256.5(upon)-259.1(minimizat)-11.5(ion.)-255.8(Likewi)-9.9(se,)-255.3(a)-258.6(sufcien)-9.1(t)-253.9(number)]TJ T* [(of)-333.6(near-optimal)-337.6(Pareto)-336.5(curves)-330(coul)-7.6(d)-325.1(b)0(e)-327.7(p)-6.5(roduced)-329.6(un)-7.2(til)-323.6(a)-332.6(bound)-328.2(on)-331.6(the)-325.5(im)-7.8(proveme)-8.7(nt)-328.7(in)-323(ener)-8.6(gy)-325.9(guara)-9.4(ntees)]TJ T* 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[(\(m)-7(inimize)-9.3(d\))-373.4(Pareto)-382(frontier,)-383.9(since)-381.2(the)-376.7(appro)-7.6(priate)-379.8(balance)-385.1(between)-381.6(these)-381.2(conce)-9.2(rns)-375.3(is)-375.4(unknow)-8.5(n)-376.3(ahead)-379.1(of)]TJ T* [(time)-281.3(and)-282.9(is)-278.6(the)-280(reason)-284.5(for)-279.4(performi)-8.7(ng)-280.4(the)-280(sweep.)-280.3(Th)-7(us,)-276.2(we)-280.4(assess)-286.1(some)-282.7(variants)-285.8(that)-277.8(are)-281(more)-283.5(conservat)-12.5(ive)]TJ 0 -1.195 TD [(and)-362.6(some)-356.7(that)-363.2(are)-360.7(less)-357.1(conse)-8.6(rvative)-363.5(from)-357.7(an)-356.1(ener)-8.6(getic)-360(standpoi)-8.9(nt,)-357.5(expecting)-12.1(,)-353.2(respect)-10.9(ively,)-358.6(less)-357.1(and)-362.6(more)]TJ 0 -1.2007 TD [(im)-7.8(pact)-254.1(on)-246.2(im)-7.8(munogeni)-8.5(city.)-249.7(We)-256.2(also)-253.5(consider)-260.3(the)-251.5(overa)-9.4(ll)-246.1(dive)-7.6(rsity)-251.5(of)-253.9(the)-251.5(designs,)-257.3(in)-249(ter)-8.8(ms)-250.9(of)-248.2(mutat)-9(ions)-251.7(that)]TJ T* [(are)-411.9(common)-7.7(ly)-402.6(emp)-7.6(loyed)-406.7(amo)-7.6(ng)-405.6(the)-405.2(variant)-10.7(s,)-406.4(as)-402.8(well)-412.6(as)-402.8(in)-408.3(their)-411.4(relative)-408.7(loca)-9.4(tions)-408.9(in)-402.6(the)-410.9(sequence)-412.8(and)]TJ T* [(str)-8.2(ucture.)]TJ /F2 1 Tf 10.959 0 0 10.959 208.8566 386.7023 Tm [(3.)-501.9(RESULTS)-330(AND)-334.3(DISCUSSIO)6.7(N)]TJ /F1 1 Tf 9.9626 0 0 9.9626 84.0755 362.8345 Tm [(We)-313.2(demo)-8.4(nstrate)-313.5(EpiSweep)-317(with)-314.1(case-st)-12.1(udy)-309.6(applicatio)-12.6(ns)-304.3(to)-311.6(two)-310.6(therape)-9.7(utic)-312(prot)-7.8(eins,)-310.8(SakSTA)-8.5(R)-307.1(\(Prot)-9.7(ein)]TJ -1.0015 -1.2007 TD [(Data)-252.3(Ba)-8(nk)-246.2([PDB])-248.9(code:)-254.8(2SAK,)-249.5(chain)-249.2(A\))-252.1(and)-248.8(Epo)-246.8(\(1EER)-10.1(,)-245.1(chain)-249.2(A\),)-246.8(previ)-10.3(ously)-246.8(target)-10(ed)-248(for)-245.2(deimm)-9.7(unization)]TJ T* [(by)-263.3(exper)-9.4(imental)-271.1(methods)-8.9(.)-256.5(I)0(t)-262.3(shoul)-7.8(d)-262.5(b)0(e)-265.1(noted)-264.4(that)-266.4(the)-262.9(side-ch)-9.1(ain)-262.9(atoms)-269.1(of)-265.3(the)-262.9(last)-261.9(residue)-270.9(\(R166\))-269.3(in)-260.4(the)-268.6(Epo)]TJ T* [(str)-8.2(ucture)-325.9(are)-326.5(missing)-329.7(excep)-9.2(t)-322.2(for)-319.2(the)-325.5(C)]TJ /F12 1 Tf 15.5011 0 TD (b)Tj /F1 1 Tf .8763 0 TD [(atom.)-324.5(The)-328.2(missing)-329.7(side-chain)-329(atom)-329.8(coord)-7.6(inates)-327.8(were)-325.5(added)-331.7(using)]TJ -16.3774 -1.2007 TD [(SCW)-8.8(RL)-336.1(\(Side-Cha)-9.7(ins)-336.3(With)-341.2(a)-332.6(Rotamer)-346.2(Library\))-340.7(\(Canutesc)-11.5(u)-330.8(e)0(t)-336.1(al.,)-336.9(2003\).)]TJ 1.0015 -1.2007 TD [(Since)-453.2(the)-450.7(previous)-452(exper)-9.4(imental)-453.2(work)-447.1(focus)-8.8(ed)-447.2(on)-445.4(iden)-7.6(tied)-448.5(immu)-7.2(nogeni)-9.1(c)-446.4(regions,)-451.6(we)-451.1(rst)-446.4(perf)-8.8(orm)]TJ -1.0015 -1.2007 TD [(anal)-9.4(ogous)-420.4(peptide)-8.7(-focused)-424.5(design)-10.3(,)-415.8(using)-423.2(the)-416.6(extensi)-9.9(on)-416.9(discusse)-10.3(d)-416.2(i)0(n)-419.7(the)-422.3(methods)-8.9(.)-415.8(For)-418.9(these)-426.8(studies,)-425.1(we)]TJ T* [(focus)-429.9(o)-6.5(n)-421.9(the)-427.9(overa)-9.4(ll)-422.5(trends)-433.4(in)-425.4(the)-427.9(energyepi)-12(tope)-428.7(landscap)-9.7(e,)-424(usin)-7(g)-421.9(E)0(p)-7(iSweep)-429.5(to)-425.4(expl)-7.6(ore)-427.2(the)-427.9(trade-)-9.2(offs)]TJ 0 -1.195 TD [(betwee)-10.9(n)-359.3(maint)-9(aining)-359(sta)-8(bility)-362.7(and)-356.9(reduc)-9.4(ing)-357.9(immu)-7.2(nogenici)-9.5(ty.)-357.5(We)-364.4(do)-360(not)-357.9(bothe)-8.4(r)-355.6(perf)-8.8(orming)-360(ener)-8.6(gy)-360(mini-)]TJ 0 -1.2007 TD [(mi)-7.8(zation)-252.7(to)-249(b)-6.5(etter)-253.9(evaluate)-257.8(these)-256(designs,)-257.3(as)-254.9(that)-249.4(woul)-9.7(d)-245.5(not)-255.4(provide)-256.6(signica)-9.9(nt)-249(additio)-9.7(nal)-251.5(insights)-255.8(into)-253.3(these)]TJ T* [(limi)-9.2(ted)-331.2(\(pept)-10.3(ide-focused)-10.3(\))-332.8(desi)-8.8(gns.)]TJ 1.0015 -1.2007 TD [(We)-301.8(then)-297.8(demonst)-8.9(rate)-295.9(that)-300.6(EpiSweep)-305.6(can)-296.1(optim)-7.2(ize)-298.8(entire)-300.2(protei)-8.2(ns,)-293.3(select)-11(ing)-295.3(optim)-7.2(al)-296.3(sets)-294.5(of)-299.4(mutation)-8.3(s)-292.2(t)0(o)]TJ -1.0015 -1.2007 TD [(hit)-281(scattered)-284.5(epitope)-8.7(s.)-275.5(Since)-282.5(the)-274.3(side)-8.8(-chains)-282.3(modeled)-282.7(by)-274.7(EpiSw)-9.5(eep)-273.3(are)-281(from)-278(disc)-8.8(rete)-278.8(sets)-277.4(of)-276.6(rigid)-278.8(rotam)-8.2(ers,)]TJ T* [(we)-320.2(better)-322.9(model)-319.2(the)-314.1(resu)-8(lting)-319.4(structure)-9.7(s)-314.9(b)0(y)-314.5(generat)-9.7(ing)-318(not)-312.3(only)-318.8(the)-319.8(Pareto)-319.4(optim)-7.2(al)-313.4(curve)-322.3(but)-318(also)-316.1(the)-319.8(four)]TJ T* 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[(strain.)-402.4(Based)-400.3(on)-394.2(T-cell)-402.4(prolera)-9.9(tion)-395.5(assays,)-399.1(they)-400.2(focused)-404.7(on)-394.2(the)-393.8(highly)-402.7(im-)]TJ -11.6941 -1.195 TD [(muno)-6.6(genic)-306.1(C3)-307.8(regi)-9.6(on,)-303.5(spannin)-11.1(g)-302.4(residue)-9.1(s)-303.6(71)-8(87.)-303.5(They)-311.9(employe)-9.5(d)-302.4(ala)-8.6(nine-scanni)-11.1(ng)-308.8(mutagenesi)-11.8(s)-303.6(t)0(o)-305.9(iden)-7.6(tify)]TJ 0 -1.2007 TD [(mutation)-8.3(s)-241(that)-243.7(reduc)-9.4(ed)-242.3(immun)-7.9(ogenicity.)-246.7(Subsequ)-7.5(ent)-245.8(prolifera)-10.5(tion)-241.9(assa)-9(ys)-241.7(then)-240.9(show)-8.2(ed)-242.3(that)-243.7(the)-245.8(response)-247.3(was)]TJ T* [(indeed)-449.1(reduced)-445.2(for)-444.4(various)-445.5(desi)-8.8(gns)-441.7(incorpor)-8.9(ating)-443.6(24)-446.2(alanine)-448.7(substitut)-8.9(ions.)-439.9(Th)-7(ey)-441.5(did)-443.2(not)-443.2(engineer)-448.7(the)]TJ T* [(redesig)-9.2(ned)-334.1(pept)-7.6(ides)-333.2(back)-342.4(into)-332.9(the)-336.9(whole)-342.3(protei)-8.2(n)-330.8(t)0(o)-334.3(test)-335.9(sta)-8(bility)-334.3(and)-339.8(activit)-8.6(y.)]TJ 1.0015 -1.2007 TD [(We)-284.7(appl)-7.6(ied)-285.7(pept)-7.6(ide-focused)-294.8(Ep)-7(iSweep)-292.9(to)-283.1(iden)-7.6(tify)-283.7(mut)-8.6(ations)-286.2(in)-288.8(the)-285.7(C3)-290.8(region)-289.9(as)-289(well)-287.4(as)-289(in)-288.8(an)-287.8(additional)]TJ -1.0015 -1.2007 TD [(region,)-318.8(which)-319.6(we)-314.5(nam)-7.6(e)-309.8(B)0(e)-8(ta,)-313.7(spanning)-319.1(residue)-9.1(s)-314.9(2438.)-317.2(We)-318.8(evaluat)-10.5(ed)-310.6(ener)-8.6(gies)-316.1(accordi)-9.7(ng)-314.5(to)-311.6(the)-319.8(deposit)-8.1(ed)]TJ T* [(SakSTA)-8.5(R)-335.5(structure)-339.8(\(2SA)-8.2(K\))-337.5(and)-334.1(appl)-7.6(ied)-336.9(homology)-336.7(lt)-7(ering)-334.7(accor)-11.1(ding)-335.9(to)-334.3(the)-336.9(family)-336.1(\(Pfa)-8(m)-334.3(PF02821\))-6.5(.)]TJ 1.0015 -1.2007 TD [(The)-299.8(C-)-8.2(terminal)-308(end)-300(of)-305.1(SakSTA)-8.5(R)-301.4(folds)-305.7(over)-302.7(perpe)-9.4(ndicula)-8.7(r)-298.7(t)0(o)-300.2(the)-302.7(C3)-307.8(peptide,)-305(appro)-7.6(ximatel)-9.3(y)-296.7(bise)-8.8(cting)-301.3(it)]TJ -1.0015 -1.195 TD [(and)-305.7(leaving)-304.7(som)-7(e)-298.5(residue)-9.1(s)-303.6(buried,)-301.7(som)-7(e)-298.5(expose)-9.3(d,)-302.7(and)-300(som)-7(e)-298.5(h)-6.5(alf-exposed)-10.3(.)-302(Warme)-9.7(rdam)-300.6(et)-302(al.)-308.1(\(2002\))-304.4(chose)]TJ 0 -1.2007 TD [(substitut)-8.9(ions)-302.9(at)-307.7(the)-302.7(posi)-7(tions)-300.7(o)-6.5(f)-298.6(C3)-307.8(underlined)-308.9(in)-305.9(the)-302.7(table)-308.8(in)-305.9(Figure)-306.2(2)-302.4(\(bottom\))-7.7(.)-302(They)-306.3(chose)-310.2(not)-306.7(to)-300.2(mutat)-9(e)]TJ T* [(the)-285.7(large)-291(hydrop)-6.6(hobics)-289.2(becau)-9.2(se)-283.3(of)-288(potential)-288.9(struct)-9.4(ural)-288.4(implica)-9.3(tions,)-284.1(b)-6.5(u)0(t)-283.1(these)-290.2(same)-290.2(residue)-9.2(s)-280.8(tend)-292.1(to)-283.1(anchor)]TJ T* [(MHC)-286(II)-278.6(binding.)-284.4(In)-282.3(particula)-11.1(r,)-276.3(F7)-6.4(6)-279.6(i)0(s)-278.6(a)-281.4(P1)-279.6(anchor)-283.3(\(see)-282.9(Met)-8.8(hods,)-283.5(Epitope)-285.6(score\))-286.4(for)-279.4(4)-279.6(epitope)-8.7(s.)-281.2(Our)-281.3(energy)]TJ T* [(evaluat)-10.5(ion)-369.2(predicts)-371.2(that)-374.6(an)-367.5(F76K)-370.4(substitut)-8.9(ion)-369.3(in)-368.5(fact)-369.9(improv)-7.1(es)-368.7(the)-371(energy,)-369(p)-6.5(ossibly)-371.7(because)-372.2(it)-371.2(is)-369.7(solvent)]TJ T* [(expose)-9.3(d.)-245.8(Thu)-7.8(s,)-247(our)-249(plan)-7.6(s)-246.7(\(Fig)-7(.)-245.1(2)0(,)-251.5(bottom)-7.9(\))-247.4(uniform)-9.9(ly)-249(choose)-254(it)-251.7(and)-248.8(obta)-7.6(in)-249(a)-247.2(better)-254.7(ener)-8.6(gy)-251.9(than)-252.3(the)-251.5(wild-typ)-8.9(e.)]TJ T* [(Over)-488.7(the)-490.5(sweep)-496.2(at)-484.1(a)-486.2()0(x)-6.4(e)0(d)-487(mutation)-8.3(al)-489.8(load,)-486(we)-490.9(see)-490.7(trends)-490.3(from)-494.2(more)-488.3(to)-488(less)-488(ener)-8.6(getically)-495.6(favorable)]TJ T* [(substitut)-8.9(ions)-263.1(with)-268.6(decreasing)-271.1(epitope)-270.5(scor)-8(e)-264.3(\(left-right)-268.1(in)-266.1(the)-262.9(g)-6.4(ure)-262.1(and)-265.8(bottom)-7.9(-up)-266(in)-260.4(the)-268.6(table\).)-266.4(We)-267.6(are)-263.9(able)]TJ 0 -1.195 TD [(to)-334.3(delete)-339.8(all)-339.7(the)-331.2(epitop)-11.9(es)-334.6(with)-336.9(either)-340(two)-339(or)-333.6(three)-336.5(subst)-9(itutions.)]TJ 1.0015 -1.2007 TD [(We)-256.2(chose)-259(also)-253.5(to)-254.7(stud)-7(y)-251.2(the)-257.2(Beta)-258.8(peptide)-259.1(becau)-9.2(se)-254.9(it)-251.7(was)-259.6(predict)-10.7(ed)-253.7(to)-254.7(be)-253.7(highly)-260.5(immunogeni)-10.6(c)-252.9(i)0(n)-254.7(our)-254.7(initial)]TJ -1.0015 -1.2007 TD [(T-cell)-345.5(epitope)-350.2(predictio)-9.3(n)-336.5(anal)-9.4(ysis,)-338.6(and)-345.5(it)-342.8(is)-335.5(als)-8(o)-336.5(struct)-9.4(urally)-343.9(quite)-346.9(different)-346.2(from)-346.3(C3.)-342.4(Beta)-344.2(sits)-341(in)-340(an)-344.8(anti-)]TJ T* [(parallel)-374.5(beta)-373.6(strand)-370.8(wi)-8.2(th)-368.5(a)-366.7(pattern)-374.9(of)-367.7(surface)-10.1(-expo)-7.6(sed)-369.5(and)-368.3(buri)-7.8(ed)-367.5(side-ch)-9.2(ains.)-373.4(The)-368.1(predict)-10.7(ed)-367.5(epitope)-372.9(and)]TJ T* 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[(note)-280.7(that)-283.5(som)-7(e)-281.4(o)0(f)-276.6(the)-285.7(mutation)-8.3(s)-280.8(are)-281(predict)-10.7(ed)-282.2(to)-277.4(be)-282.2(stability)-285.4(enhanc)-9.9(ing)-283.9(\(though)-283.2(again,)-283.7(this)-282.9(is)-284.3(before)-285.3(energy)]TJ 0 -1.195 TD [(minimi)-8.5(zation\).)]TJ /F5 1 Tf 10.959 0 0 10.959 107.6031 135.7795 Tm [(3.2.)-496.9(Erythropoietin)-331.8(\(Epo\))-327.3(peptides)]TJ /F1 1 Tf 9.9626 0 0 9.9626 117.5811 117.8646 Tm [(Erythropo)-7.7(ietin)-389.5(\(Epo\))-388.8(has)-386.5(therape)-9.7(utic)-391.6(use)-386.5(in)-385.6(treating)-389.8(anem)-10.2(ia)-387.3(but)-386.3(unfortun)-7.1(ately)-388.5(induces)-394.1(an)-384.6(immu)-7.2(ne)-384.6(re-)]TJ -1.0015 -1.2007 TD [(sponse)-270.5(in)-271.7(some)-271.3(patients)-275.2(\(Indiveri)-270.5(and)-271.5(Murd)-7(aca,)-269.8(2002\).)-273.6(Based)-269.4(on)-269(an)-270.8(intensive)-276(analysis)-273.7(of)-271(peptides)-272.5(spanning)]TJ T* [(the)-325.5(entire)-334.3(protein)-8.9(,)-324.7(Tangri)-329.6(et)-324.7(al.)-330.8(\(2005\))-327.2(iden)-7.6(tifed)-326.1(two)-333.3(highly)-328.8(immunogeni)-10.6(c)-326.9(regions,)-332.1(spanning)-330.5(101115)-335.4(and)]TJ T* [(136150.)-295.9(They)-289.2(engi)-7.6(neered)-296.4(four)-291.5(variants)-297.2(targeting)-299.5(the)-291.4(anchor)-294.7(residue)-9.1(s)-286.5(o)0(f)-288(iden)-7.6(tied)-294.9(T-cell)-294.3(epitope)-8.7(s)-286.5(i)0(n)-288.8(thes)-8.8(e)]TJ T* [(regions:)-306.8(L102P)-8.5(/S146D)-306.4(\(named)-303.9(G2\))-8.2(,)-296.3(T107D)-7.6(/S146D)-306.4(\(G3\),)-307.2(L102G/T107)-8.2(D/S)-8.2(146D)-302.9(\(G4\),)-301.5(and)-305.7(L102S)-8.5(/T107D/)]TJ ET q 432.919 0 0 183.968 107.603 538.299 cm /Im2 Do Q BT /F2 1 Tf 8.9663 0 0 8.9663 107.6031 522.3116 Tm [(FIG.)-334.8(2.)]TJ /F1 1 Tf 4.1162 0 TD 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~#\UڶچލFi4@N<.m*z+kZ5ƘZa 턞q`ԭ(v銣4yNUP>\[Eֿ{'p-iZ b*UتݹK$dd@9 rBCèJ- i`T-`kk{ˁ$!bHӛ^MNت|ϗK۫`xdwVBQ0Y(3( @6VʯMi(/ϩxšPœՊZgL4](v jח:uyQ*]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb~c^4"O *.4Ccs9,a>Ӿ-'jjU0Z+%u$鶎2WSO]TIxT@m2-gxiuȦӪKWqTZiw6Z{'!MUߕ~U]v*UثWb]v*UثWb]ct5%si4Qn]Tȏr1U;2S˚2@nllV{́vKx@Bٙ lkKo2n\—x"1I#$uVqv*UثWb>5XteHZSle|U꿤^cm-,KyNΤxqV^=H[WS# d㊠/ <^GzI,N T>تkMmtm"bFmj "3aE%a*fˎ3:@52s 2!=yV(H*t^[8y2(a<0;Db]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثUqCx4%FتiFȎdW(E OACXh=ZWӊfYʞCPԭ=U\UثWb]v*UثWb]v*UثWb76QУ>B`9SOѼ;9,u2[u"]Y<Tfޘ?w~\Vk$a%Y%yP{i8dثTu7wֶRW64X@TK3(D.B}V3[ĒIk!gPLlTCLUbUJG;a[kzeUֺbҧ(Vr Ωޣv_k]UJZMF CgF*ǼbXsY dӋ%y"*/6`F*ȴSP+KiI$ j*j:_Kw&wc]O7@r@hFڄ3 3bm^?2[i+O%<”R#PBO>L7^`/ȬJ՚+i٣S rBw+W-.-y"fQQ!jqU]mŬSDKg)S$L ʒi_RWCu-Q\3Kf:e ;W|U}^_1OO= yNZeiVTjWW*!$$1qWyUt[BLX)N(ɂ&B5QW0~V֕@yoVմk{2}n^tQe*]5{;.鬮'T;FXSS@HX87iphkGi(gf[eBTC1TnZifNЗV*398IBz U#5ڮnښ菤D!̸Ht'uߡ\UZ~Cַ1^9njխ.HaؕQl+LU]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb[WM~u YDLOaPt9"{VyLY*"TLWb]v*UثWb]v*UثWb]v*UثWb[=WL+GwNbv i*k.eb>ϐ6+V#snMY-bҮkƐzrԡ~˹b[򞟡$HoO,dS%-1Tv*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]y'߷.g^_>u>OK^Ik{⫱Wb?%w?tzJioӿ_1TJs&_GOT_>r߳F^ث5?-z5?yPߘ[OWqTk?wƴT Qywe'LU S)W?؋=Kz_￿gws|w>}C"mۯ~MUˏ[̴rgb?jt~׾).п|q,>7Uߚ?0?-?o?⨏/z_f\T3T +q%.|q?ޙ:b蘫Wb^mOL''WLU:?ĺWG(Ώ??7O5*3y?_7g(fWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb_ endstream endobj 36 0 obj <> endobj 37 0 obj <>/Font<>/ProcSet[/PDF/Text/ImageB/ImageC]/ExtGState<>>> endobj 38 0 obj <>stream /GS1 gs BT /F1 1 Tf 9.9626 0 0 9.9626 117.5811 559.2188 Tm 0 0 0 rg 0 Tc 0 Tw [(Previously,)-370.5(we)-360.1(had)-362.6(rede)-8.6(signed)-363.1(SakST)-9.5(AR)-363(based)-361.4(on)-365.7(a)-361.1(one-)-359.6(and)-362.6(two-bo)-7.5(dy)-360(seque)-8.6(nce)-364.4(potential)-10.1(,)-358.9(sampling)]TJ -1.0015 -1.2007 TD [(linear)-300.2(combina)-9.5(tions)-295.1(of)-293.7(thi)-7.8(s)-292.2(seque)-8.6(nce)-296.1(potential)-300.3(and)-300(the)-297.1(epitope)-299(score)-300.8(\(Parker)-298.6(et)-296.3(al.,)-297.1(2011b\))-6.6(.)-290.6(I)0(t)-296.5(i)0(s)-295.7(interest)-9.8(ing)]TJ T* [(to)-283.1(compare)-289.3(and)-282.9(cont)-7.6(rast)-283.9(the)-280(seque)-8.6(nce-)-8.6(guided)-282.3(plan)-7.6(s)-280.8(with)-285.7(these)-284.5(struct)-9.4(ure-gui)-8.2(ded)-282.9(\(and)-285.6(Pareto)-285.2(optim)-7.2(al\))-282(plan)-7.6(s.)]TJ T* [(For)-396.1(exam)-10.2(ple,)-399.9(both)-398.5(tend)-400.3(to)-396.9(choose)-407.7(Y24K)-397.9(and)-402.4(V112A,)-404.7(along)-401(with)-399.5(some)-402.2(substitut)-8.9(ion)-397.7(at)-398.7(M26)-402.6(\()-82.4(M26D)-401.6(for)]TJ T* 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[(whi)-9(ch)-333.4(we)-337.3(describ)-9.2(e)-332.6(i)0(n)-334.3(the)-336.9(followi)-8.1(ng)-337.3(paragrap)-9.7(h.)]TJ 1.0015 -1.195 TD [(It)-324.9(should)-327.2(be)-322(no)-7.2(ted)-325.5(that)-323.3(for)-324.9(Epo,)-326.8(the)-325.5(mutants)-330.3(are)-326.5(predicted)-332.7(to)-323(have)-325.3(lower)-327.2(ener)-8.6(gies)-327.5(\(median)]TJ /F7 1 Tf 37.3471 0 TD (-)Tj /F1 1 Tf .7227 0 TD [(4422)-168.1(kcal/)]TJ -39.0713 -1.2007 TD [(mol)-8.6(;)-265.3(the)-274.3(energy)-271.9(valu)-7.6(es)-272(of)-271(all)-271.4(designs)-274(are)-269.6(depi)-7.6(cted)-271.2(in)-271.7(Fig.)-272.1(7\))-271(than)-269.4(the)-274.3(wild-ty)-8.2(pe)-270.8(\()]TJ /F7 1 Tf 32.3223 0 TD (-)Tj /F1 1 Tf .7227 0 TD [(3859)-168.1(kcal)-9.4(/mol\).)-271.3(This)-274.3(was)]TJ -33.045 -1.2007 TD [(no)-7.2(t)-293.7(the)-297.1(case)-299.8(for)-296.5(SakSTA)-8.5(R)-295.7(\(wild-type:)]TJ /F7 1 Tf 15.8709 0 TD (-)Tj /F1 1 Tf .7227 0 TD [(2154)-168.1(kcal)-9.4(/mol,)-297(median)-299(mutant)]TJ /F7 1 Tf 12.7582 0 TD (-)Tj /F1 1 Tf .717 0 TD [(2160)-173.8(kcal/mol)-10.1(\).)-293.3(We)-296.1(inve)-7.6(stigated)]TJ -30.0689 -1.2007 TD [(the)-388.1(cause)-391.6(of)-384.8(thes)-8.8(e)-383.8(lower)-389.8(ener)-8.6(gies.)-384.7(Of)-388.7(the)-388.1(293)-389.2(designs,)-388.2(237)-389.2(of)-384.8(them)-392.4(have)-387.9(a)-383.8(V82E)-388.1(subst)-9(itution.)-386.7(\(See)-394.8(the)]TJ T* [(Su)-6.4(ppleme)-8.7(ntary)-266.4(Material)-274.1(for)-262.3(the)-268.6(other)-266.4(mutat)-9(ion)-261.1(frequ)-9.6(encies.\))-267.4(In)-265.3(addi)-7.6(tion)-264.7(to)-266.1(reducing)-270.5(the)-262.9(epitope)-270.5(scor)-8(e)-264.3(b)0(y)-263.3(6)0(,)]TJ T* [(thi)-7.8(s)-326.3(mutation)-338.4(introdu)-7.2(ces)-331.4(a)-326.9(negativ)-8.7(ely)-331.2(charg)-9.4(ed)-327.7(residue)-333.5(that)-334.7(makes)-336.5(a)-326.9(strong)-334.9(chargech)-10.3(arge)-333(intera)-10(ction)-329.8(with)]TJ T* [(the)-302.7(positivel)-9.5(y)-296.7(charged)-302.9(adja)-9.4(cent)-299.6(residue)-305.1(K82.)-302.5(We)-296.1(u)-6.5(sed)-295.5(TIN)-8(KER)-301(to)-300.2(model)-302.1(this)-300(single)-303.3(mutation)-304.2(\(Fig.)-297.6(8\))-299.4(and)]TJ T* [(found)-273.2(that)-266.4(it)-268.8(provides)-275.6(a)]TJ /F7 1 Tf 9.8105 0 TD (-)Tj /F1 1 Tf .7227 0 TD [(146)-167.3(kcal)-9.4(/mol)-268.2(contrib)-8.9(ution)-265.4(to)-266.1(the)-268.6(ener)-8.6(gy.)-263.7(We)-273.3(note)-269.4(that)-266.4(such)-273.5(stabilizat)-10.9(ion)-266.8(has)-267(been)]TJ ET q 360.926 0 0 101.424 109.02 620.844 cm /Im6 Do Q BT /F2 1 Tf 8.9663 0 0 8.9663 74.0976 604.8566 Tm [(FIG.)-322.1(6.)]TJ /F1 1 Tf 4.0972 0 TD [(Pareto-optimal)-321(plans)-315(in)-319.2(the)-314.8(energyepitope)-317(landscape)-320.3(for)-319.9(the)-314.8(full)-318.5(Epo)-314.5(protein.)-316.1(See)-318.1(Figure)-314.5(4)-315.7(for)-313.6(description.)]TJ ET q 288.933 0 0 205.228 216.057 70.242 cm /Im7 Do Q BT /F2 1 Tf 8.9663 0 0 8.9663 74.0976 175.2945 Tm [(FIG.)-315.8(7.)]TJ /F1 1 Tf 4.0972 0 TD [(Energyepitope)-314.4(scores)-310.4(of)]TJ -4.0972 -1.2266 TD [(energy-minimized)-342.3(Epo)-333.5(designs.)]TJ /F2 1 Tf 9.9626 0 0 9.9626 74.0976 737.4045 Tm [(16)-7.2(2)]TJ 35.3326 0 TD [(PAR)-10(KER)-338.8(ET)-335.3(AL.)]TJ ET endstream endobj 44 0 obj <>stream Adobed         s!1AQa"q2B#R3b$r%C4Scs5D'6Tdt& EFVU(eufv7GWgw8HXhx)9IYiy*:JZjzm!1AQa"q2#BRbr3$4CS%cs5DT &6E'dtU7()󄔤euFVfvGWgw8HXhx9IYiy*:JZjz ?N*UثWb]v*UثWb]v*UثWb]v*UثWbR?5} x鸸b#%!E^@ի'-Tϗ 4tt^9&Ѣ@ Z?AU]}5O<Ơi,rV7~.]xX'% XȌOm_v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثV[io7>5iDeHMk\U^AvInţn-ObثWbD e+x?UCqTܱ4ZjVZ\ۮث ]v*UثWb]v*UثWb]v*UثWbR6y^y-5k8g&~yP{) dFEb|Th}T~YKu[@FuPZjsC@;*&Eb ."PCv?Պ:Qv=.σrXk 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[(Jones,)-302.4(T.D.,)-295.4(Phillips,)-299.4(W.J.,)-301.7(Smith,)-295.2(B.J.,)-304.5(et)-296.3(al.)-299.2(2005.)-298.1(Identication)-302.7(and)-298.1(removal)-296.1(of)-298.8(a)-299.1(promiscuous)-300.4(CD4)]TJ /F7 1 Tf 41.3582 0 TD (+)Tj /F1 1 Tf 1.018 0 TD [(T)-302.8(cell)-295.5(epitope)]TJ -41.3708 -1.2266 TD [(from)-329.3(the)-333.8(C1)-338.9(domain)-329.5(of)-336.7(factor)-333.6(VIII.)]TJ /F5 1 Tf 14.8272 0 TD [(J.)-333.6(Thromb.)-338.2(Haemost.)]TJ /F1 1 Tf 8.9027 0 TD [(3,)-337.5(9911000.)]TJ -24.7352 -1.2203 TD [(Kessler,)-332.8(M.,)-328.5(Goldsmith,)-328.4(D.,)-324.8(and)-329.7(Schellekens,)-331.2(H.)-328.2(2006.)-323.4(Immunogenicity)-329.6(of)-330.4(biopharmaceuticals.)]TJ /F5 1 Tf 39.1704 0 TD [(Nephrology,)-328.9(Dialysis,)]TJ -38.1651 -1.2203 TD (Transplantation)Tj /F1 1 Tf 6.7782 0 TD [(21,)-330.7(v912.)]TJ -7.7835 -1.2266 TD 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