Abstract
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.
Highlights
Allostery—the process by which biological macromolecules transmit the effect of a stimulus at one site to a physically distinct site—is among the most important and heavily studied properties of proteins [1,2]
Molecular dynamics (MD) simulations have emerged as a valuable complement to experimental methods [8] in the study of allostery because they capture the motion of proteins in full atomic detail
Because the crystal structure had an antagonist bound in the orthosteric site, we focused on several allosteric modulators known to affect the binding affinity of orthosteric antagonists, the widely used antagonist N-methyl scopolamine (NMS)
Summary
Allostery—the process by which biological macromolecules transmit the effect of a stimulus (typically ligand binding) at one site to a physically distinct site—is among the most important and heavily studied properties of proteins [1,2]. Molecular dynamics (MD) simulations have emerged as a valuable complement to experimental methods [8] in the study of allostery because they capture the motion of proteins in full atomic detail These simulations—whose initial development several decades ago was among the achievements recognized by the 2013 Nobel Prize in Chemistry—predict the position of every atom in a biomolecular system as a function of time using Newtonian mechanics [9]. MD simulations have proven useful in the investigation of allostery for two reasons They provide an all-atom description of protein behavior with very high resolution in both space (sub-angstrom) and time (femtoseconds). We hope that this article will prove useful both to structural biologists beginning to use MD and to MD practitioners turning to the study of allostery
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