Kilambi Krishna Praneeth, Reddy Kavan, Gray Jeffrey J
Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.
Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America; Program in Molecular Biophysics, Johns Hopkins University, Baltimore, Maryland, United States of America.
PLoS Comput Biol. 2014 Dec 11;10(12):e1004018. doi: 10.1371/journal.pcbi.1004018. eCollection 2014 Dec.
Protein-protein interactions depend on a host of environmental factors. Local pH conditions influence the interactions through the protonation states of the ionizable residues that can change upon binding. In this work, we present a pH-sensitive docking approach, pHDock, that can sample side-chain protonation states of five ionizable residues (Asp, Glu, His, Tyr, Lys) on-the-fly during the docking simulation. pHDock produces successful local docking funnels in approximately half (79/161) the protein complexes, including 19 cases where standard RosettaDock fails. pHDock also performs better than the two control cases comprising docking at pH 7.0 or using fixed, predetermined protonation states. On average, the top-ranked pHDock structures have lower interface RMSDs and recover more native interface residue-residue contacts and hydrogen bonds compared to RosettaDock. Addition of backbone flexibility using a computationally-generated conformational ensemble further improves native contact and hydrogen bond recovery in the top-ranked structures. Although pHDock is designed to improve docking, it also successfully predicts a large pH-dependent binding affinity change in the Fc-FcRn complex, suggesting that it can be exploited to improve affinity predictions. The approaches in the study contribute to the goal of structural simulations of whole-cell protein-protein interactions including all the environmental factors, and they can be further expanded for pH-sensitive protein design.
蛋白质-蛋白质相互作用取决于许多环境因素。局部pH条件通过可电离残基的质子化状态影响相互作用，这些残基在结合时会发生变化。在这项工作中，我们提出了一种pH敏感对接方法pHDock，它可以在对接模拟过程中实时采样五个可电离残基（天冬氨酸、谷氨酸、组氨酸、酪氨酸、赖氨酸）的侧链质子化状态。pHDock在大约一半（79/161）的蛋白质复合物中产生成功的局部对接漏斗，其中包括19例标准RosettaDock失败的情况。pHDock的表现也优于两个对照案例，即pH 7.0对接或使用固定的、预先确定的质子化状态。平均而言，与RosettaDock相比，排名靠前的pHDock结构具有更低的界面均方根偏差，并且恢复了更多天然界面残基-残基接触和氢键。使用计算生成的构象集合增加主链灵活性，进一步改善了排名靠前的结构中的天然接触和氢键恢复。尽管pHDock旨在改进对接，但它也成功预测了Fc-FcRn复合物中很大的pH依赖性结合亲和力变化，这表明它可用于改进亲和力预测。该研究中的方法有助于实现包括所有环境因素在内的全细胞蛋白质-蛋白质相互作用的结构模拟目标，并且可以进一步扩展用于pH敏感蛋白质设计。
