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For this reason, buried \u201cunsatisfied\u201d polar groups making no hydrogen bonds are very rare in proteins. Efficiently representing the energetic cost of unsatisfied hydrogen bonds with a pairwise-decomposable energy term during protein design is challenging since whether or not a group is satisfied depends on all of its neighbors. Here we describe a method for assigning a pairwise-decomposable energy to sidechain rotamers such that following combinatorial sidechain packing, buried unsaturated polar atoms are penalized. The penalty can be any quadratic function of the number of unsatisfied polar groups, and can be computed very rapidly. We show that inclusion of this term in Rosetta sidechain packing calculations substantially reduces the number of buried unsatisfied polar groups.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1008061","type":"journal-article","created":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T13:41:02Z","timestamp":1615210862000},"page":"e1008061","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":31,"title":["Protein sequence optimization with a pairwise decomposable penalty for buried unsatisfied hydrogen bonds"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6910-6255","authenticated-orcid":true,"given":"Brian","family":"Coventry","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Baker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,3,8]]},"reference":[{"key":"pcbi.1008061.ref001","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/B978-0-12-381270-4.00019-6","article-title":"ROSETTA3: an object-oriented software suite for the simulation and design of macromolecules","volume":"487","author":"A Leaver-Fay","year":"2011","journal-title":"Methods Enzymol"},{"key":"pcbi.1008061.ref002","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1002\/(SICI)1097-0134(19990501)35:2<133::AID-PROT1>3.0.CO;2-N","article-title":"Effective energy function for proteins in solution","volume":"35","author":"T Lazaridis","year":"1999","journal-title":"Proteins Struct Funct Bioinforma"},{"key":"pcbi.1008061.ref003","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1021\/ct500864r","article-title":"Combined Covalent-Electrostatic Model of Hydrogen Bonding Improves Structure Prediction with Rosetta","volume":"11","author":"MJ O\u2019Meara","year":"2015","journal-title":"J Chem Theory Comput"},{"key":"pcbi.1008061.ref004","doi-asserted-by":"crossref","first-page":"e8140","DOI":"10.1371\/journal.pone.0008140","article-title":"Generating Triangulated Macromolecular Surfaces by Euclidean Distance Transform","volume":"4","author":"D Xu","year":"2009","journal-title":"PLOS ONE"},{"key":"pcbi.1008061.ref005","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1089\/cmb.2013.0071","article-title":"Protein Depth Calculation and the Use for Improving Accuracy of Protein Fold Recognition","volume":"20","author":"D Xu","year":"2013","journal-title":"J Comput Biol"},{"key":"pcbi.1008061.ref006","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/0022-2836(87)90679-6","article-title":"Structure of ubiquitin refined at 1.8\u00c5resolution","volume":"194","author":"S Vijay-Kumar","year":"1987","journal-title":"J Mol Biol"},{"key":"pcbi.1008061.ref007","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1093\/bioinformatics\/btq007","article-title":"PyRosetta: a script-based interface for implementing molecular modeling algorithms using Rosetta","volume":"26","author":"S Chaudhury","year":"2010","journal-title":"Bioinformatics"},{"key":"pcbi.1008061.ref008","unstructured":"Schr\u00f6dinger, LLC. 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