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（由适用提供）：离子是生物分子系统的重要组成部分。所有蛋白质的三分之一都包含金属离子作为结构或功能目的的组成部分。负电荷磷酸基团的结合无处不在地参与调节，信号转导和其他各种过程。尽管是有关蛋白质离子系统的大量实验结构和热力学信息，但我们对特定识别机制和蛋白质/离子选择性的理解仍然难以捉摸。使用经典模型对蛋白质离子系统的计算和理论研究非常挑战，因为缺乏准确且可计算的经典模型来模拟蛋白质中的离子。我们建议使用量子机械计算和经典的分子动力学模拟系统地研究二价金属离子和含有配体与蛋白质的结合。我们将使用量子机械能分解来严格检查蛋白质离子相互作用中不同类型的物理力，并开发一种新的经典模型，以准确描述离子与蛋白质/水环境之间的物理相互作用。通过这种新的经典模型，我们将获得对分子动力学模拟特异性和选择性基础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，这项研究将对我们在生物分子结构和功能方面的科学知识提高科学知识有广泛的影响。这项研究还将导致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的设计。