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This process, of coupled folding and binding (CFaB), is a fundamental part of many important biological processes. Structure\u2010based models have proven themselves capable of revealing fundamental aspects of how CFaB occurs, however, typical methods to enhance the sampling of these transitions, such as replica exchange, do not adequately sample the transition state region of this extremely rare process. Here, we use a variant of Umbrella Sampling to enforce sampling of the transition states of CFaB of HdeA monomers at neutral pH, an extremely rare process that occurs over timescales ranging from seconds to hours. Using high resolution sampling in the transition state region, we cluster states along the principal transition path to obtain a detailed description of coupled binding and folding for the HdeA dimer, revealing new insight into the ensemble of states that are accessible to client recognition. We then demonstrate that exchanges between umbrella sampling windows, as done in previous work, significantly improve relaxation in variables orthogonal to the restraints used. Altogether, these results show that Window\u2010Exchange Umbrella Sampling is a promising approach for systems that exhibit flexible binding, and can reveal transition state ensembles of these systems in high detail. \u00a9 2015 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/jcc.24004","type":"journal-article","created":{"date-parts":[[2015,8,6]],"date-time":"2015-08-06T19:56:58Z","timestamp":1438891018000},"page":"587-594","source":"Crossref","is-referenced-by-count":20,"title":["Coupled folding and binding with 2D Window\u2010Exchange Umbrella Sampling"],"prefix":"10.1002","volume":"37","author":[{"given":"Alex","family":"Dickson","sequence":"first","affiliation":[{"name":"Department of Chemistry The University of Michigan Ann Arbor Michigan 48109"}]},{"given":"Logan S.","family":"Ahlstrom","sequence":"additional","affiliation":[{"name":"Department of Chemistry The University of Michigan Ann Arbor Michigan 48109"}]},{"suffix":"III","given":"Charles 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