Abstract
Small molecules, such as solvent, substrate, and cofactor molecules, are key players in enzyme catalysis. Computational methods are powerful tools for exploring the dynamics and thermodynamics of these small molecules as they participate in or contribute to enzymatic processes. In-depth knowledge of how small molecule interactions and dynamics influence protein conformational dynamics and function is critical for progress in the field of enzyme catalysis. Although numerous computational studies have focused on enzyme–substrate complexes to gain insight into catalytic mechanisms, transition states and reaction rates, the dynamics of solvents, substrates, and cofactors are generally less well studied. Also, solvent dynamics within the biomolecular solvation layer play an important part in enzyme catalysis, but a full understanding of its role is hampered by its complexity. Moreover, passive substrate transport has been identified in certain enzymes, and the underlying principles of molecular recognition are an area of active investigation. Enzymes are highly dynamic entities that undergo different conformational changes, which range from side chain rearrangement of a residue to larger-scale conformational dynamics involving domains. These events may happen nearby or far away from the catalytic site, and may occur on different time scales, yet many are related to biological and catalytic function. Computational studies, primarily molecular dynamics (MD) simulations, provide atomistic-level insight and site-specific information on small molecule interactions, and their role in conformational pre-reorganization and dynamics in enzyme catalysis. The review is focused on MD simulation studies of small molecule interactions and dynamics to characterize and comprehend protein dynamics and function in catalyzed reactions. Experimental and theoretical methods available to complement and expand insight from MD simulations are discussed briefly.
Highlights
Proteins are nature’s best catalysts to accelerate specific biochemical reactions via catalytically reactive atoms embedded within a folded structure
This review provides an overview of recent progress towards understanding the role of small molecule interactions in enzyme catalysis using molecular dynamics (MD) simulations as a crucial tool to characterize, comprehend and exploit natural catalysts
A combined study of quasi-elastic neutron scattering and MD simulations showed that the translational diffusion of hydration water promotes large amplitude motions in proteins to facilitate the dynamical transitions required for biological activity [115]
Summary
Proteins are nature’s best catalysts to accelerate specific biochemical reactions via catalytically reactive atoms embedded within a folded structure. Experimental and theoretical studies have demonstrated that catalytic function is mediated by protein dynamics and interactions with small molecules such as solvents, cofactors, and substrates [10,11,12,13,14]. Computational investigations involving small molecule interactions with enzymes commonly target (a) protein solvation to comprehend protein stability and flexibility, (b) protein-binding pockets and active sites to understand molecular recognition, binding affinity, and catalytic mechanisms, and (c) enzyme–substrate complexes to explore conformational heterogeneity and dynamics during catalysis. These play roles in protein conformational dynamics and transitions, ligand binding and release, catalytic mechanisms, and allosteric regulation in the catalytic reaction. Effect of Small Molecule Interactions on Protein Structure, Function, and Dynamics
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