基于弹性网络模型的蛋白质变构路径与关键残基识别研究

目的 变构效应在蛋白质生物学功能执行过程中发挥着重要的调控作用,如何基于蛋白质空间结构,有效识别变构信号的传播路径和关键的残基位点是蛋白质结构-功能关系研究领域的热点科学问题。方法 本研究利用基于弹性网络模型（elastic network model,ENM）的力分布计算方法,通过分析蛋白质对外力的响应过程,来识别体系的变构路径以及变构过程中的关键残基。在该方法中,对蛋白质的关键变构位点施加外力,通过对体系形变以及内力分布情况的分析,有效识别与外力承载区域形变相耦合的关键残基,从而得到力信号在蛋白质结构内的传播路径。结果 利用该方法研究了人类磷酸甘油酸激酶（human phosphoglycerate kinase,hPGK）和蛋白质酪氨酸磷酸酶（protein tyrosine phosphatase,PTP）PDZ2结构域的变构调控路径和关键残基。对于hPGK,识别出从底物结合位点到铰链区的两条变构信号传导路径。对于PTP PDZ2,也成功识别出从配体结合位点传递到蛋白质远端的两条长程变构调控路径。计算结果与实验和分子动力学（molecular dynamics,MD）模拟得到的结果一致。结论 本研究为蛋白质体系关键残基识别及变构路径研究提供了有效的分析方法。

Identification of Protein Allosteric Pathway and Related Key Residues by Using Elastic Network Model

Objective Allostery plays important roles in regulating protein biological functions. How to effectively identify the allosteric signal transduction pathway and the related key residues from the tertiary structure of proteins is a hot scientific problem in the research field of protein structure-function relationship.Methods In the present work, a method based on elastic network model (ENM) combined with force distribution calculation was used to investigate the response of proteins to the external loading forces, and then the allosteric pathway and associated key residues in proteins were identified based on the analysis of internal force distribution. In this method, external forces were exerted on the allosteric site of the protein, and then the deformations and internal force distributions within the protein in response to the external loading forces were analyzed. Based on these analyses, the key sites that are coupled with the deformation of the force-loading region were identified, and the transduction pathway of the force signals in the protein was obtained.Results By using the proposed method, two proteins, the human phosphoglycerate kinase (hPGK) and protein tyrosine phosphatase (PTP) PDZ2 domain, were investigated to identify the allosteric pathway and the related key residues in the systems. For hPGK, two allosteric pathways were identified, which mediate the transduction of force signals from the substrate binding site to the hinge region of the protein. For PTP PDZ2, two long-range allosteric pathways, from the ligand binding site to the distantly opposite side of the protein, were also successfully revealed. The calculation results are consistent with the experimental observations and the results obtained with molecular dynamics simulations.Conclusion This study provides an effective method for the identification of key residues and allosteric pathway in proteins.