Ensemble Molecular Dynamics of a Protein-Ligand Complex: ResidualInhibitor Entropy Enhances Drug Potency in ButyrylcholinesteraseEric J Sorin1*, Walter Alvarado2, Samantha Cao1, Amethyst Radcliffe2, Phuc La1 and Yi An1
- *Corresponding Author:
- Sorin EJ
Department of Chemistry and Biochemistry California State University Long Beach 1250 Bellflower Blvd. Long Beach
California 90840-9401, USA
E-mail: [email protected]
Received date: December 06, 2016; Accepted date: January 05, 2017; Published date: January 08, 2017
Citation: Sorin EJ, Alvarado W, Cao S, Radcliffe A, La P, et al. (2017) Ensemble Molecular Dynamics of a Protein-Ligand Complex: Residual Inhibitor Entropy Enhances Drug Potency in Butyrylcholinesterase. Bioenergetics 6:145. doi: 10.4172/2167-7662.1000145
Copyright: © 2017 Sorin EJ, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Butyrylcholinesterase is a key enzyme that catalyzes the hydrolysis of the neurotransmitter acetylcholine and shows an increased activity in patients suffering from Alzheimer’s disease (AD), making this enzyme a primary target in treating AD. Central to this problem, and to similar scenarios involving biomolecular recognition, is our understanding of the nature of the protein-ligand complex. The butyrylcholinesterase enzyme was studied via all-atom, explicit solvent, ensemble molecular dynamics simulations sans inhibitor and in the presence of three dialkyl phenyl phosphate inhibitors of known potency to a cumulative sampling of over 40 μs. Following relaxation of these ensembles to conformational equilibria, binding modes for each inhibitor were identified. While classical models, which assume significant reduction in both protein and ligand conformational entropies, continue to be favored in contemporary studies, our observations contradict those assumptions: bound ligands occupy many conformational states, thereby stabilizing the complex, while also promoting protein flexibility.