Ensemble Molecular Dynamics of a Protein-Ligand Complex: Residual Inhibitor Entropy Enhances Drug Potency in Butyrylcholinesterase.

Bioenergetics : open access Pub Date : 2017-01-01 Epub Date: 2017-01-08 DOI:10.4172/2167-7662.1000145
Eric J Sorin, Walter Alvarado, Samantha Cao, Amethyst Radcliffe, Phuc La, Yi An
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引用次数: 3

Abstract

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 the relaxation of these ensembles to conformational equilibria, binding modes for each inhibitor were identified. While classical models, which assume significant reduction in 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.

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Abstract Image

Abstract Image

蛋白质-配体复合物的整体分子动力学:残余抑制剂熵增强了丁基胆碱酯酶的药物效力。
丁基胆碱酯酶是催化神经递质乙酰胆碱水解的关键酶,在阿尔茨海默病(AD)患者中显示出活性增加,使该酶成为治疗AD的主要靶点。这个问题的核心,以及涉及生物分子识别的类似场景,是我们对蛋白质-配体复合物本质的理解。对丁基胆碱酯酶进行了全原子、外显溶剂、系综分子动力学模拟,在无抑制剂和三种已知效价的二烷基苯基磷酸抑制剂存在的情况下,累积采样超过40 μs。随着这些组合松弛到构象平衡,确定了每个抑制剂的结合模式。虽然经典模型假设蛋白质和配体构象熵显著降低,在当代研究中继续受到青睐,但我们的观察结果与这些假设相矛盾:结合的配体占据了许多构象状态,从而稳定了复合物,同时也促进了蛋白质的灵活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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