Specificity and Selectivity in Protein-Ion Binding

 描述(申请人提供)：离子是生物分子系统的重要组成部分。三分之一的蛋白质含有金属离子，作为结构或功能的组成部分。带负电荷的磷酸基团的结合广泛地参与调控、信号转导和其他各种过程。虽然有太多关于蛋白质-离子体系的实验结构和热力学信息，但我们对特定识别和蛋白质/离子选择性的机制仍然难以理解。由于缺乏精确且易于计算的经典模型来模拟蛋白质中的离子，使用经典模型对蛋白质-离子体系进行计算和理论研究是非常具有挑战性的。我们建议用量子力学计算和经典分子动力学模拟方法系统地研究二价金属离子和含磷配体与蛋白质的结合。我们将利用量子力学能量分解严格考察蛋白质-离子相互作用中不同类型的物理力，并发展一个新的经典模型来准确描述离子与蛋白质/水环境之间的物理相互作用。有了这个新的经典模型，我们将从分子动力学模拟中获得对专一性和选择性背后的热力学驱动力的定量理解。鉴于蛋白质-离子结合的基本重要性，这项研究将对促进我们对生物分子结构和功能中的离子的科学知识产生广泛的影响。这项研究还将导致计算方法和公共软件工具，使蛋白质-离子结合的准确预测成为可能，并最终设计出针对特定离子的新分子和蛋白质。

 DESCRIPTION (provided by applicant): Ions are essential components of biomolecular systems. One third of all proteins contain metal ions as integral parts for structural or functiona purposes. Binding of negatively charged phosphate groups is ubiquitously involved in regulation, signal transduction and various other processes. Whereas is a plethora of experimental structural and thermodynamic information about protein-ion systems, our understanding of the mechanism for specific recognition and protein/ion selectivity remains elusive. Computational and theoretical studies of protein-ion systems using classical models are very challenging due to the lack of accurate and yet computationally tractable classical models for simulating ions in proteins. We propose to systematically investigate the binding of divalent metal ions and phosphate containing ligands to proteins using quantum mechanical calculations and classical molecular dynamics simulations. We will rigorously examine the different types of physical forces in protein-ion interactions using quantum mechanical energy decomposition, and develop a new classical model to accurately describe the physical interactions between ions and protein/water environment. With this new classical model, we will obtain quantitative understanding of the thermodynamic driving forces underlying the specificity and selectivity from molecular dynamics simulations. Given the fundamental importance of protein-ion binding, this research will have a broad impact on advancing our scientific knowledge about ions in biomolecular structure and functions. This research will also lead to computational methods and public software tools that will enable accurate prediction of protein-ion binding and ultimately design of new molecules and proteins targeting specific ions.