Role and Mechanism of ATP Hydrolysis in Actin

ATP 水解在肌动蛋白中的作用和机制

• 批准号: 8494411
• 负责人: Isaiah Sumner
• 金额: $ 4.92万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8494411
• 关键词: ATP phosphohydrolase; Actins; Adenosine Diphosphate; Adenosine Triphosphate; Affect; Affinity; Amino Acids; Antineoplastic Agents; Area; Behavior; Binding; Biochemistry; Biological; Cell division; Cellular Structures; Cereals; Computer Simulation; Computers; Coupling; Development; Disease; Drug Design; Energy-Generating Resources; Environment; Event; F-Actin; Filament; G Actin; Genetic; Glean; Growth; Hydrolysis; Investigation; Knowledge; Link; Measures; Methodology; Methods; Microfilaments; Modeling; Muscle; Muscle Contraction; Mutation; Myopathy; Nature; Nucleotides; Organelles; Pattern; Play; Polymers; Process; Property; Proteins; Protons; Reaction; Research Training; Role; Scheme; Solutions; Speed; Structural Protein; Structure; System; Techniques; Time; Water; base; cell motility; design; improved; inorganic phosphate; insight; interest; molecular dynamics; monomer; protonation; reaction rate; scaffold; simulation; theories; tool

DESCRIPTION (provided by applicant): Actin is a highly abundant protein that has a conserved structure across many species. It occurs in a monomer and polymer form and is involved in cell motility, division, organelle transport and muscle contraction. Actin binds to adenosine triphosphate (ATP) and will also catalyze its hydrolysis to adenosine diphosphate (ADP). The rates for this reaction are greatly different for free actin monomers and polymerized actin monomers. Additionally, the state of this nucleotide - ATP, ADP, or ADP plus an inorganic phosphate - plays a critical role in the structure, function and dynamics of actin. Despite experimental and computational scrutiny, there remain many questions about the effect of the bound nucleotide on actin polymers as well as the mechanism of actin catalyzed-ATP hydrolysis. In addition to its role in actin function, the hydrolysis of ATP to ADP is also the main source of energy used to drive biological reactions. Due to its importance to biochemistry, the exact nature of the source of this energy in different environments (protein and solution) remains an area of active debate. Our knowledge in these areas can be improved through the development, application and eventual combination of two different molecular dynamics (MD) methods. The main benefit of MD simulations is that they contain the atomistic details of the problem of interest but they suffer from their inability to allow bonds to break and reform. However, a reactive MD simulation of ATP hydrolysis can be constructed via the proposed multistate molecular dynamics (MS-MD) methodology. MS-MD is a generalization of the multistate empirical valence bond (MS-EVB) theory, which has hitherto been mainly applied to proton solvation and transport in water and has been recently extended to amino acid protonation. However, atomistic MD is computationally expensive for large systems like polymerized actin. This bottleneck can be overcome if some or all of the actin polymer is treated with a simplified, coarse-grained (CG) model using the multiscale coarse-graining (MS-CG) scheme, which is derived from the interactions of the full, atomistic-scale model. The combination of MS-MD and MS-CG will allow for the first detailed, accurate, fully reactive MD simulations of the nucleotide related properties of actin including actin-catalyzed ATP hydrolysis.

描述（由申请人提供）：肌动蛋白是一种高度丰富的蛋白质，在许多物种中具有保守的结构。它以单体和聚合物形式存在，参与细胞运动、分裂、细胞器运输和肌肉收缩。肌动蛋白与三磷酸腺苷 (ATP) 结合，也会催化其水解为二磷酸腺苷 (ADP)。对于游离肌动蛋白单体和聚合肌动蛋白单体来说，该反应的速率有很大不同。此外，这种核苷酸的状态（ATP、ADP 或 ADP 加无机磷酸盐）在肌动蛋白的结构、功能和动力学中起着至关重要的作用。尽管进行了实验和计算审查，但关于结合核苷酸对肌动蛋白聚合物的影响以及肌动蛋白催化 ATP 水解的机制仍然存在许多问题。除了在肌动蛋白功能中发挥作用外，ATP 水解为 ADP 也是驱动生物反应的主要能量来源。由于其对生物化学的重要性，不同环境（蛋白质和溶液）中这种能量来源的确切性质仍然是一个活跃争论的领域。 我们在这些领域的知识可以通过两种不同分子动力学（MD）方法的开发、应用和最终组合来提高。 MD 模拟的主要好处是它们包含了感兴趣问题的原子细节，但它们的缺点是无法允许债券断裂和重组。然而，可以通过所提出的多态分子动力学 (MS-MD) 方法构建 ATP 水解的反应性 MD 模拟。 MS-MD 是多态经验价键 (MS-EVB) 理论的推广，该理论迄今为止主要应用于质子在水中的溶剂化和传输，最近已扩展到氨基酸质子化。然而，对于聚合肌动蛋白等大型系统来说，原子 MD 的计算成本很高。如果使用多尺度粗粒度 (MS-CG) 方案（源自完整的原子相互作用）对部分或全部肌动蛋白聚合物进行简化的粗粒度 (CG) 模型处理，则可以克服这一瓶颈。 -比例模型。 MS-MD 和 MS-CG 的结合将允许对肌动蛋白的核苷酸相关特性（包括肌动蛋白催化的 ATP 水解）进行首次详细、准确、完全反应性的 MD 模拟。