Abstract
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.
Highlights
Through tightly controlled cellular pH, posttranslational modification by protons regulates biological function [1]
PHDock outperforms RosettaDock in 67% (20/30) of the cases where the top-ranked pHsensitive docking algorithm (pHDock) model recovers a nonstandard protonation state observed in the native bound complex (S5 Figure). pHDock performs better than RosettaDock in 64% (7/11) of the cases where the top-ranked pHDock produces a nonstandard protonation state different from the one observed in the native bound complex illustrating the importance of dynamic protonation states
We examined the fraction of the native interface hydrogen bonds recovered in the top-ranked models. pHDock recovers more than one-fifth of the native interface hydrogen bonds in only 33% of the targets from the dataset, while RosettaDock performs worse, recovering the same fraction in just 22% of the targets (Fig. 5C)
Summary
Through tightly controlled cellular pH, posttranslational modification by protons regulates biological function [1]. We develop a pH-sensitive protein-protein docking algorithm and demonstrate that it can improve prediction accuracy and recover pH-dependent binding effects. Computational docking algorithms are playing an increasingly influential role in driving large-scale protein-protein interactions (PPI) surveys [7,8] and genome-wide interactome studies [9], but they need to accommodate sensitivity to local environment pH for improved reliability. In real systems protonation states are affected by the solution pH and the change in the local environment of the ionizable surface residues due to the receptor-ligand interactions during binding. In docking algorithms, residue pKa values vary depending on the conformations of the ligand relative to the receptor. Dynamic evaluation of the protonation states during docking using pKa calculation algorithms on-the-fly is more true to the physical process of binding and may improve prediction accuracy
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