Rigid Residue Scan Simulations Systematically Reveal Residue Entropic Roles in Protein Allostery.
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.
Department of Chemistry, Center for Drug Discovery, Design, and Delivery (CD4), Center for Scientific Computation, Southern Methodist University, Dallas, Texas, United States of America.
Robert
R
Kalescky
Department of Chemistry, Center for Drug Discovery, Design, and Delivery (CD4), Center for Scientific Computation, Southern Methodist University, Dallas, Texas, United States of America.
Hongyu
H
Zhou
Department of Chemistry, Center for Drug Discovery, Design, and Delivery (CD4), Center for Scientific Computation, Southern Methodist University, Dallas, Texas, United States of America.|Department of Pharmaceutical Sciences, University of North Texas System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, Texas, United States of America.
Jin
J
Liu
Department of Chemistry, Center for Drug Discovery, Design, and Delivery (CD4), Center for Scientific Computation, Southern Methodist University, Dallas, Texas, United States of America.
Peng
http://orcid.org/0000-0002-2488-0239
P
Tao
D000494:Allosteric Regulation; D019295:Computational Biology; D003198:Computer Simulation; D019277:Entropy; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D054731:PDZ Domains; D025341:Principal Component Analysis; D011485:Protein Binding; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13 / Q000737:chemistry / Q000378:metabolism; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*
D008024:Ligands; D011506:Proteins; C516742:PTPN13 protein, human; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13