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In this study, we improved MixMD using human immunodeficiency virus type\u20101 protease (HIVp) as the test case. We used three probe\u2013water solutions (acetonitrile\u2013water, isopropanol\u2013water, and pyrimidine\u2013water), first at 50% w\/w concentration and later at 5% v\/v. Paradoxically, better mapping was achieved by using fewer probes; 5% simulations gave a superior signal\u2010to\u2010noise ratio and far fewer spurious hot spots than 50% MixMD. Furthermore, very intense and well\u2010defined probe occupancies were observed in the catalytic site and potential allosteric sites that have been confirmed experimentally. The Eye site, an allosteric site underneath the flap of HIVp, has been confirmed by the presence of a 5\u2010nitroindole fragment in a crystal structure. MixMD also mapped two additional hot spots: the Exo site (between the Gly16\u2010Gly17 and Cys67\u2010Gly68 loops) and the Face site (between Glu21\u2010Ala22 and Val84\u2010Ile85 loops). The Exo site was observed to overlap with crystallographic additives such as acetate and dimethyl sulfoxide that are present in different crystal forms of the protein. Analysis of crystal structures of HIVp in different symmetry groups has shown that some surface sites are common interfaces for crystal contacts, which means that they are surfaces that are relatively easy to desolvate and complement with organic molecules. MixMD should identify these sites; in fact, their occupancy values help establish a solid cut\u2010off where \u201cdruggable\u201d sites are required to have higher occupancies than the crystal\u2010packing faces. \u00a9 2015 Wiley Periodicals, Inc. Biopolymers 105: 21\u201334, 2016.<\/jats:p>","DOI":"10.1002\/bip.22742","type":"journal-article","created":{"date-parts":[[2015,9,19]],"date-time":"2015-09-19T08:52:09Z","timestamp":1442652729000},"page":"21-34","source":"Crossref","is-referenced-by-count":53,"title":["Identifying binding hot spots on protein surfaces by mixed\u2010solvent molecular dynamics: HIV\u20101 protease as a test case"],"prefix":"10.1002","volume":"105","author":[{"given":"Peter M. 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