{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T02:45:52Z","timestamp":1792205152811,"version":"4.4.0"},"reference-count":43,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2012,11,29]],"date-time":"2012-11-29T00:00:00Z","timestamp":1354147200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"NIH","award":["RO1-GM73960"],"award-info":[{"award-number":["RO1-GM73960"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Protein Science"],"published-print":{"date-parts":[[2013,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The accurate design of new protein\u2013protein interactions is a longstanding goal of computational protein design. However, most computationally designed interfaces fail to form experimentally. This investigation compares five previously described successful <jats:italic>de novo<\/jats:italic> interface designs with 158 failures. Both sets of proteins were designed with the molecular modeling program Rosetta. Designs were considered a success if a high\u2010resolution crystal structure of the complex closely matched the design model and the equilibrium dissociation constant for binding was less than 10 \u03bc<jats:italic>M<\/jats:italic>. The successes and failures represent a wide variety of interface types and design goals including heterodimers, homodimers, peptide\u2010protein interactions, one\u2010sided designs (i.e., where only one of the proteins was mutated) and two\u2010sided designs. The most striking feature of the successful designs is that they have fewer polar atoms at their interfaces than many of the failed designs. Designs that attempted to create extensive sets of interface\u2010spanning hydrogen bonds resulted in no detectable binding. In contrast, polar atoms make up more than 40% of the interface area of many natural dimers, and native interfaces often contain extensive hydrogen bonding networks. These results suggest that Rosetta may not be accurately balancing hydrogen bonding and electrostatic energies against desolvation penalties and that design processes may not include sufficient sampling to identify side chains in preordered conformations that can fully satisfy the hydrogen bonding potential of the interface.<\/jats:p>","DOI":"10.1002\/pro.2187","type":"journal-article","created":{"date-parts":[[2012,11,8]],"date-time":"2012-11-08T16:31:39Z","timestamp":1352392299000},"page":"74-82","source":"Crossref","is-referenced-by-count":242,"title":["A comparison of successful and failed protein interface designs highlights the challenges of designing buried hydrogen bonds"],"prefix":"10.1002","volume":"22","author":[{"given":"P. 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