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Protein-protein docking with dynamic residue protonation states.

Kilambi KP, Reddy K, Gray JJ - PLoS Comput. Biol. (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.

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.

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Distributions of native and model interface hydrogen bonds.Kernel density estimate curves for the number of (A) interface hydrogen bonds and (B) interface hydrogen bonds involving ionizable residues in the top-scoring models generated using pHDock (orange) and RosettaDock (grey), and the native crystal complexes (black) across the complete Docking Benchmark dataset. Frequency histograms of the fraction of (C) recovered interface hydrogen bonds and (D) recovered interface hydrogen bonds involving ionizable residues in the top-scoring models.
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pcbi-1004018-g005: Distributions of native and model interface hydrogen bonds.Kernel density estimate curves for the number of (A) interface hydrogen bonds and (B) interface hydrogen bonds involving ionizable residues in the top-scoring models generated using pHDock (orange) and RosettaDock (grey), and the native crystal complexes (black) across the complete Docking Benchmark dataset. Frequency histograms of the fraction of (C) recovered interface hydrogen bonds and (D) recovered interface hydrogen bonds involving ionizable residues in the top-scoring models.

Mentions: To further assess the quality of the predicted top-ranked structures, we examined the receptor-ligand interface hydrogen bonds (henceforth referred to as simply ‘interface hydrogen bonds’). Previous surveys found 8–13 interface hydrogen bonds in each protein–protein complex [37], [38]. Using Rosetta's hydrogen bonding definition, the native crystal complexes in our dataset contain 6.4±3.5 interface hydrogen bonds on average (Fig. 5A). In comparison, the top pHDock models are involved in 5.1±2.5 interface hydrogen bonds, while the top RosettaDock models form only 3.4±2.1 interface hydrogen bonds. As pHDock primarily focuses on ionizable residues, we also calculated the number of interface hydrogen bonds containing such residues as donors or acceptors. The native complexes contain 3.5±2.6 ionizable interface hydrogen bonds (Fig. 5B). Encouragingly, the top pHDock models are found to form an identical 3.5±2.4 ionizable interface hydrogen bonds, while the top RosettaDock models form only 2.1±1.6 hydrogen bonds.


Protein-protein docking with dynamic residue protonation states.

Kilambi KP, Reddy K, Gray JJ - PLoS Comput. Biol. (2014)

Distributions of native and model interface hydrogen bonds.Kernel density estimate curves for the number of (A) interface hydrogen bonds and (B) interface hydrogen bonds involving ionizable residues in the top-scoring models generated using pHDock (orange) and RosettaDock (grey), and the native crystal complexes (black) across the complete Docking Benchmark dataset. Frequency histograms of the fraction of (C) recovered interface hydrogen bonds and (D) recovered interface hydrogen bonds involving ionizable residues in the top-scoring models.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263365&req=5

pcbi-1004018-g005: Distributions of native and model interface hydrogen bonds.Kernel density estimate curves for the number of (A) interface hydrogen bonds and (B) interface hydrogen bonds involving ionizable residues in the top-scoring models generated using pHDock (orange) and RosettaDock (grey), and the native crystal complexes (black) across the complete Docking Benchmark dataset. Frequency histograms of the fraction of (C) recovered interface hydrogen bonds and (D) recovered interface hydrogen bonds involving ionizable residues in the top-scoring models.
Mentions: To further assess the quality of the predicted top-ranked structures, we examined the receptor-ligand interface hydrogen bonds (henceforth referred to as simply ‘interface hydrogen bonds’). Previous surveys found 8–13 interface hydrogen bonds in each protein–protein complex [37], [38]. Using Rosetta's hydrogen bonding definition, the native crystal complexes in our dataset contain 6.4±3.5 interface hydrogen bonds on average (Fig. 5A). In comparison, the top pHDock models are involved in 5.1±2.5 interface hydrogen bonds, while the top RosettaDock models form only 3.4±2.1 interface hydrogen bonds. As pHDock primarily focuses on ionizable residues, we also calculated the number of interface hydrogen bonds containing such residues as donors or acceptors. The native complexes contain 3.5±2.6 ionizable interface hydrogen bonds (Fig. 5B). Encouragingly, the top pHDock models are found to form an identical 3.5±2.4 ionizable interface hydrogen bonds, while the top RosettaDock models form only 2.1±1.6 hydrogen bonds.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.

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.

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