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An explicit description of hydrogen atoms is generally needed in order to analyze the binding mode of particular ligands or to calculate the associated binding energies. Due to the large number of degrees of freedom resulting from different chemical moieties and the high degree of mutual dependence this problem is anything but trivial. In addition to an efficient algorithm to take care of the complexity resulting from complicated hydrogen bonding networks, a robust chemical model is needed to describe effects such as tautomerism and ionization consistently. We present a novel method for the placement of hydrogen coordinates in protein-ligand complexes which takes tautomers and protonation states of both protein and ligand into account. Our method generates the most probable hydrogen positions on the basis of an optimal hydrogen bonding network using an empirical scoring function. The high quality of our results could be verified by comparison to the manually adjusted Astex diverse set and a remarkably low rate of undesirable hydrogen contacts compared to other tools.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1758-2946-6-12","type":"journal-article","created":{"date-parts":[[2014,4,3]],"date-time":"2014-04-03T03:03:02Z","timestamp":1396494182000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":182,"title":["Protoss: a holistic approach to predict tautomers and protonation states in protein-ligand complexes"],"prefix":"10.1186","volume":"6","author":[{"given":"Stefan","family":"Bietz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sascha","family":"Urbaczek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Schulz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Rarey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,4,3]]},"reference":[{"issue":"1","key":"635_CR1","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1093\/nar\/28.1.235","volume":"28","author":"HM Berman","year":"2000","unstructured":"Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The protein data bank. 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