Specificity and Selectivity in Protein-Ion Binding

蛋白质-离子结合的特异性和选择性

• 批准号: 9062465
• 负责人: JAY PONDER
• 金额: $ 29.14万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9062465
• 关键词: Acute; Adenine Nucleotides; Anions; Binding; Binding Proteins; Binding Sites; Biosensor; Cells; Charge; Chemistry; Computing Methodologies; Data; Development; Diagnostic; Disease; Drug Targeting; Electrostatics; Enzymes; Fingerprint; Free Energy; Goals; Health; Ions; Knowledge; Lead; Ligands; Link; Malignant Neoplasms; Mechanics; Metal Ion Binding; Metalloproteins; Metals; Modeling; Molecular; Molecular Models; Mutation; Nerve Degeneration; Penetration; Phosphoric Monoester Hydrolases; Phosphorylated Peptide; Phosphotransferases; Play; Positioning Attribute; Potential Energy; Process; Protein Engineering; Proteins; Public Health; Pyridoxal Phosphate; Regulation; Research; Shapes; Signal Transduction; Signaling Protein; Software Tools; Specificity; Structure; Surface; System; Theoretical Studies; Thermodynamics; Trace Elements; Transition Elements; base; chemical property; computer studies; computerized tools; design; divalent metal; driving force; experience; inorganic phosphate; molecular dynamics; molecular modeling; novel therapeutics; open source; physical property; quantum; src Homology Region 2 Domain; therapeutic protein; therapeutic target; water environment

 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.

 描述（由申请人提供）：离子是生物分子系统的基本组成部分。三分之一的蛋白质含有金属离子作为结构或功能目的的组成部分。带负电荷的磷酸基团的结合普遍参与调节、信号转导和各种其他过程。尽管有大量关于蛋白质-离子系统的实验结构和热力学信息，但我们对特异性识别和蛋白质/离子选择性机制的理解仍然是难以捉摸的。由于缺乏精确的，但计算上易于处理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-离子系统进行计算和理论研究是非常具有挑战性的。我们建议使用量子力学计算和经典分子动力学模拟系统地研究二价金属离子和含磷酸根的配体与蛋白质的结合。我们将使用量子力学能量分解严格检查蛋白质-离子相互作用中不同类型的物理力，并开发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。通过这个新的经典模型，我们将从分子动力学模拟中获得对特异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重要性，这项研究将对推进我们关于生物分子结构和功能中离子的科学知识产生广泛的影响。这项研究还将产生计算方法和公共软件工具，从而能够准确预测蛋白质-离子结合，并最终设计出针对特定离子的新分子和蛋白质。