Understanding Protein-Ligand Recogntion

描述(由申请人提供)：准确预测波动的蛋白质环境如何识别分子配体一直是计算化学和生物物理学中长期追求的挑战。本项目的目标是开发和应用实用的全原子分子动力学模拟方法来研究蛋白质环境变化如何影响蛋白质-配体识别。该项目尤其受到我们以正交空间采样方案为代表的新型采样方法开发的鼓舞，该方案可以唯一地实现聚焦(化学)变化的运动及其耦合环境响应的同步加速，例如构象转变和润湿/去湿过程。这项研究包括三个具体目标：(1)了解蛋白质环境如何变化与蛋白质-配体结合，并实现配体相对结合亲和力的准确排序；(2)能够同时预测蛋白质-配体绝对结合亲和力和结合复杂结构；(3)阐明波动的酶如何识别紧凑的过渡态类似物结合及其天然底物。

DESCRIPTION (provided by applicant): Accurately predicting how fluctuating protein environments recognize molecular ligands have been a long-pursued challenge in computational chemistry and biophysics. The objective of this project is to develop and employ practical all-atom molecular dynamics simulation methods to study how protein environment changes govern protein-ligand recognition. This project is particularly encouraged by our novel sampling method developments, represented by the orthogonal space sampling scheme, which can uniquely enable synchronous acceleration of the motion of a focused (chemical) change and its coupled environmental responses, for instance conformational transitions and wetting/dewetting processes. This study includes three specific goals: (1) to understand how protein environment changes couple with protein-ligand binding and to realize accurate ranking of ligand relative binding affinities; (2) to enable simultaneous prediction of protein-ligand absolute binding affinities and binding complex structures; and (3) to elucidate how fluctuating enzymes recognize tight transition state analogue binders versus their natural substrates.