Rigid Residue Scan Simulations Systematically Reveal Residue Entropic Roles in Protein Allostery.

Robert Kalescky,Jin Liu,Peng Tao,Hongyu Zhou,Dennis R Livesay

doi:10.1371/journal.pcbi.1004893

Abstract

Intra-protein information is transmitted over distances via allosteric processes. This ubiquitous protein process allows for protein function changes due to ligand binding events. Understanding protein allostery is essential to understanding protein functions. In this study, allostery in the second PDZ domain (PDZ2) in the human PTP1E protein is examined as model system to advance a recently developed rigid residue scan method combining with configurational entropy calculation and principal component analysis. The contributions from individual residues to whole-protein dynamics and allostery were systematically assessed via rigid body simulations of both unbound and ligand-bound states of the protein. The entropic contributions of individual residues to whole-protein dynamics were evaluated based on covariance-based correlation analysis of all simulations. The changes of overall protein entropy when individual residues being held rigid support that the rigidity/flexibility equilibrium in protein structure is governed by the La Châtelier’s principle of chemical equilibrium. Key residues of PDZ2 allostery were identified with good agreement with NMR studies of the same protein bound to the same peptide. On the other hand, the change of entropic contribution from each residue upon perturbation revealed intrinsic differences among all the residues. The quasi-harmonic and principal component analyses of simulations without rigid residue perturbation showed a coherent allosteric mode from unbound and bound states, respectively. The projection of simulations with rigid residue perturbation onto coherent allosteric modes demonstrated the intrinsic shifting of ensemble distributions supporting the population-shift theory of protein allostery. Overall, the study presented here provides a robust and systematic approach to estimate the contribution of individual residue internal motion to overall protein dynamics and allostery.

Highlights

Allostery is the process by which signals are transmitted from distal ligand binding sites to functional sites in proteins
The all-atom Root-Mean-Square Deviation (RMSD) for the unperturbed unbound and bound states of PDZ2 are shown in Fig 1, which indicates that both structures are stable throughout the simulations
We further developed a recently proposed rigid residue scan (RRS) method through combination of configurational entropy calculation and principal component analysis (PCA) to systematically evaluate the contribution of internal degrees of freedom of individual residue to overall protein dynamics and potential allostery upon ligand binding

Summary

Introduction

Allostery is the process by which signals are transmitted from distal ligand binding sites to functional sites in proteins. The concept of allostery originated from early attempts to explain the fact that the binding of oxygen molecules to hemoglobin deviates from the typical Michaelis-Menten kinetics model.[1,2,3] Following the term “allosteric” being coined and reviewed during early 60’s,[4, 5] two protein allostery theories were proposed and referred to as the Monod−Wyman−Changeux (MWC)[6] and Koshland−Neḿ ethy−Filmer (KNF)[7] models In these models, allostery theories were formed based on significant conformational changes of hemoglobin observed in crystallographic structures. The binding signal is assumed to be transmitted through protein conformational change

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Discussion

Conclusion