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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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Docking predictions for xylanase – TAXI-IA complex.Docking plots generated by (A) RosettaDock, and (B) pHDock at pH 4.6. Grey, orange, and red points represent incorrect, acceptable-, and medium- quality predictions, respectively. Discrimination scores are shown in the bottom right corner of the plots. (C) Interface of the top-scoring pHDock prediction (medium accuracy) superimposed on the crystal complex (grey) (2B42 [32]). Predicted orientation of the TAXI-IA inhibitor and xylanase, cyan and green, respectively; critical His-374 residue from TAXI-IA, spheres; xylanase active site and other critical binding site residues, sticks.
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pcbi-1004018-g002: Docking predictions for xylanase – TAXI-IA complex.Docking plots generated by (A) RosettaDock, and (B) pHDock at pH 4.6. Grey, orange, and red points represent incorrect, acceptable-, and medium- quality predictions, respectively. Discrimination scores are shown in the bottom right corner of the plots. (C) Interface of the top-scoring pHDock prediction (medium accuracy) superimposed on the crystal complex (grey) (2B42 [32]). Predicted orientation of the TAXI-IA inhibitor and xylanase, cyan and green, respectively; critical His-374 residue from TAXI-IA, spheres; xylanase active site and other critical binding site residues, sticks.

Mentions: Fig. 2 shows sample plots for the Triticum aestivum xylanase inhibitor-I (TAXI-I) in complex with Bacillus subtilis xylanase crystallized at a pH of 4.6 (PDB: 2B42 [32]). The y-axis represents the interface score (Isc), an approximation of the binding free energy, normalized by the difference between the 5th and 95th percentile scores. The x-axis quantifies deviation from the native complex using interface RMSD (Irmsd). Each point on the plot represents a single docking model and is colored based on the CAPRI structural quality rating [33] (see Methods). The interface of the top-scoring pHDock-generated structure (Fig. 2B) is just 1.7 Å from the native interface, compared to 4.7 Å for the RosettaDock-generated structure (Fig. 2A). While RosettaDock does not generate any structures better than acceptable quality, pHDock produces a structure with higher native residue-residue contact recovery qualifying as medium quality.


Protein-protein docking with dynamic residue protonation states.

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

Docking predictions for xylanase – TAXI-IA complex.Docking plots generated by (A) RosettaDock, and (B) pHDock at pH 4.6. Grey, orange, and red points represent incorrect, acceptable-, and medium- quality predictions, respectively. Discrimination scores are shown in the bottom right corner of the plots. (C) Interface of the top-scoring pHDock prediction (medium accuracy) superimposed on the crystal complex (grey) (2B42 [32]). Predicted orientation of the TAXI-IA inhibitor and xylanase, cyan and green, respectively; critical His-374 residue from TAXI-IA, spheres; xylanase active site and other critical binding site residues, sticks.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1004018-g002: Docking predictions for xylanase – TAXI-IA complex.Docking plots generated by (A) RosettaDock, and (B) pHDock at pH 4.6. Grey, orange, and red points represent incorrect, acceptable-, and medium- quality predictions, respectively. Discrimination scores are shown in the bottom right corner of the plots. (C) Interface of the top-scoring pHDock prediction (medium accuracy) superimposed on the crystal complex (grey) (2B42 [32]). Predicted orientation of the TAXI-IA inhibitor and xylanase, cyan and green, respectively; critical His-374 residue from TAXI-IA, spheres; xylanase active site and other critical binding site residues, sticks.
Mentions: Fig. 2 shows sample plots for the Triticum aestivum xylanase inhibitor-I (TAXI-I) in complex with Bacillus subtilis xylanase crystallized at a pH of 4.6 (PDB: 2B42 [32]). The y-axis represents the interface score (Isc), an approximation of the binding free energy, normalized by the difference between the 5th and 95th percentile scores. The x-axis quantifies deviation from the native complex using interface RMSD (Irmsd). Each point on the plot represents a single docking model and is colored based on the CAPRI structural quality rating [33] (see Methods). The interface of the top-scoring pHDock-generated structure (Fig. 2B) is just 1.7 Å from the native interface, compared to 4.7 Å for the RosettaDock-generated structure (Fig. 2A). While RosettaDock does not generate any structures better than acceptable quality, pHDock produces a structure with higher native residue-residue contact recovery qualifying as medium quality.

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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