Departments of Chemistry, ‡Molecular Biology & Biochemistry, §Molecular Biophysics Program, and ∥Department of Computer Science, Wesleyan University , Middletown, Connecticut 06459, United States of America.
J Phys Chem B. 2017 Jun 8;121(22):5509-5514. doi: 10.1021/acs.jpcb.7b02083. Epub 2017 May 25.
Conformational selection and induced fit are well-known contributors to ligand binding and allosteric effects in proteins. Molecular dynamics (MD) simulations now enable the theoretical study of protein-ligand binding in terms of ensembles of interconverting microstates and the population shifts characteristic of "dynamical allostery." Here we investigate protein-ligand binding and allostery based on a Markov state model (MSM) with states and rates obtained from all-atom MD simulations. As an exemplary case, we consider the single domain protein par-6 PDZ with and without ligand and allosteric effector. This is one of the smallest proteins in which allostery has been experimentally observed. In spite of the increased complexity intrinsic to a statistical ensemble perspective, we find that conformational selection and induced fit mechanisms can be readily identified in the analysis. In the nonallosteric pathway, MD-MSM shows that PDZ binds ligand via conformational selection. However, the allosteric pathway requires an activation step that involves a conformational change induced by the allosteric effector Cdc42. Once in the allosterically activated state, we find that ligand binding can proceed by conformational selection. Our MD-MSM model predicts that allostery in this and possibly other systems involves both induced fit and conformational selection, not just one or the other.
构象选择和诱导契合是蛋白质配体结合和变构效应的已知贡献因素。分子动力学 (MD) 模拟现在可以根据可相互转换的微观状态集合以及“动态变构”的特征种群转移来理论研究蛋白质-配体结合。在这里，我们基于具有从全原子 MD 模拟获得的状态和速率的马尔可夫状态模型 (MSM) 研究蛋白质-配体结合和变构。作为一个示例案例，我们考虑了具有和没有配体和变构效应物的单个域蛋白 par-6 PDZ。这是在实验中观察到变构的最小蛋白质之一。尽管统计集合视角内在地增加了复杂性，但我们发现，在分析中可以很容易地识别构象选择和诱导契合机制。在非变构途径中，MD-MSM 表明 PDZ 通过构象选择结合配体。然而，变构途径需要一个激活步骤，该步骤涉及变构效应物 Cdc42 诱导的构象变化。一旦处于变构激活状态，我们发现配体结合可以通过构象选择进行。我们的 MD-MSM 模型预测，在这个系统和可能的其他系统中，变构涉及诱导契合和构象选择，而不仅仅是其中之一。
