Alam Nawsad, Goldstein Oriel, Xia Bing, Porter Kathryn A, Kozakov Dima, Schueler-Furman Ora
Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
School of Computer Sciences and Engineering, The Hebrew University, Jerusalem, Israel.
PLoS Comput Biol. 2017 Dec 27;13(12):e1005905. doi: 10.1371/journal.pcbi.1005905. eCollection 2017 Dec.
Peptide-protein interactions contribute a significant fraction of the protein-protein interactome. Accurate modeling of these interactions is challenging due to the vast conformational space associated with interactions of highly flexible peptides with large receptor surfaces. To address this challenge we developed a fragment based high-resolution peptide-protein docking protocol. By streamlining the Rosetta fragment picker for accurate peptide fragment ensemble generation, the PIPER docking algorithm for exhaustive fragment-receptor rigid-body docking and Rosetta FlexPepDock for flexible full-atom refinement of PIPER docked models, we successfully addressed the challenge of accurate and efficient global peptide-protein docking at high-resolution with remarkable accuracy, as validated on a small but representative set of peptide-protein complex structures well resolved by X-ray crystallography. Our approach opens up the way to high-resolution modeling of many more peptide-protein interactions and to the detailed study of peptide-protein association in general. PIPER-FlexPepDock is freely available to the academic community as a server at http://piperfpd.furmanlab.cs.huji.ac.il.
肽-蛋白质相互作用在蛋白质-蛋白质相互作用组中占很大比例。由于高度灵活的肽与大受体表面的相互作用涉及巨大的构象空间，对这些相互作用进行精确建模具有挑战性。为应对这一挑战，我们开发了一种基于片段的高分辨率肽-蛋白质对接协议。通过简化用于准确生成肽片段集的Rosetta片段选择器、用于穷举片段-受体刚体对接的PIPER对接算法以及用于对PIPER对接模型进行灵活全原子优化的Rosetta FlexPepDock，我们成功应对了在高分辨率下准确、高效地进行全局肽-蛋白质对接的挑战，且具有显著的准确性，这在一小部分但具有代表性的通过X射线晶体学解析良好的肽-蛋白质复合物结构上得到了验证。我们的方法为更多肽-蛋白质相互作用的高分辨率建模以及肽-蛋白质结合的详细研究开辟了道路。PIPER-FlexPepDock作为服务器可免费提供给学术界，网址为http://piperfpd.furmanlab.cs.huji.ac.il 。
