Revealing Atomic-Level Mechanisms of Protein Allostery with Molecular Dynamics Simulations.
Molecular dynamics (MD) simulations have become a powerful and popular method for the study of protein allostery, the widespread phenomenon in which a stimulus at one site on a protein influences the properties of another site on the protein. By capturing the motions of a protein's constituent atoms, simulations can enable the discovery of allosteric binding sites and the determination of the mechanistic basis for allostery. These results can provide a foundation for applications including rational drug design and protein engineering. Here, we provide an introduction to the investigation of protein allostery using molecular dynamics simulation. We emphasize the importance of designing simulations that include appropriate perturbations to the molecular system, such as the addition or removal of ligands or the application of mechanical force. We also demonstrate how the bidirectional nature of allostery-the fact that the two sites involved influence one another in a symmetrical manner-can facilitate such investigations. Through a series of case studies, we illustrate how these concepts have been used to reveal the structural basis for allostery in several proteins and protein complexes of biological and pharmaceutical interest.
Department of Computer Science, Stanford University, Stanford, California, United States of America.
Samuel
S
Hertig
Department of Computer Science, Stanford University, Stanford, California, United States of America.|Biophysics Program, Stanford University, Stanford, California, United States of America.
Naomi R
0000-0002-8310-8708
NR
Latorraca
Department of Computer Science, Stanford University, Stanford, California, United States of America.|Biophysics Program, Stanford University, Stanford, California, United States of America.|Department of Molecular and Cellular Physiology, Stanford University, Stanford, California, United States of America.|Institute for Computational and Mathematical Engineering, Stanford University, Stanford, California, United States of America.
Ron O
0000-0002-6418-2793
RO
Dror
D018829:Adhesins, Bacterial / Q000737:chemistry / Q000378:metabolism; D000494:Allosteric Regulation; D000495:Allosteric Site; D019295:Computational Biology; D003198:Computer Simulation; D015195:Drug Design; D005353:Fibronectins / Q000737:chemistry / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D043585:Receptor, Muscarinic M2 / Q000737:chemistry / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000378:metabolism
D018829:Adhesins, Bacterial; D005353:Fibronectins; D008024:Ligands; D011506:Proteins; D043585:Receptor, Muscarinic M2; D018343:Receptors, Adrenergic, beta-2; D020962:Heterotrimeric GTP-Binding Proteins