Specificity and Selectivity in Protein-Ion Binding

蛋白质-离子结合的特异性和选择性

基本信息

批准号：
8860357
负责人：
JAY PONDER
金额：
$ 30.46万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
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/8860357
关键词：
Acute Adenine Nucleotides Anions Binding Binding Sites Biosensor Cells Charge Chemistry Computing Methodologies Data Development Diagnostic Disease Drug Targeting Electrostatics Enzymes Fingerprint Free Energy Goals Ions Knowledge Lead Ligands Link Malignant Neoplasms Mechanics Metal Ion Binding Metalloproteins Metals Modeling Molecular Molecular Models Mutation Nerve Degeneration Penetration Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphorylated Peptide Phosphotransferases Play Positioning Attribute Potential Energy Process Protein Binding 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 open source physical property public health relevance quantum src Homology Region 2 Domain therapeutic protein therapeutic target water environment

项目摘要

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。虽然有大量关于蛋白质离子系统的实验结构和热力学信息，但我们对蛋白质离子特异性识别和蛋白质/离子选择性机制的理解仍然难以捉摸。由于缺乏精确且易于计算处理的经典模型来模拟蛋白质中的离子，使用经典模型的系统非常具有挑战性。我们建议使用量子力学计算和经典分子动力学系统地研究二价金属离子和含磷酸盐的配体与蛋白质的结合。我们将使用量子机械能分解严格检查蛋白质-离子相互作用中的不同类型的物理力，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。将获得鉴于分子动力学模拟的特异性和选择性背后的热力学驱动力，定量研究将对提高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。还带来了计算方法和公共软件工具，这些工具将能够准确预测蛋白质离子结合，并最终设计针对特定离子的新分子和蛋白质。