Approaches to computing diffusion rates in proteins from transition path theory

从转变路径理论计算蛋白质扩散速率的方法

• 批准号: 8663929
• 负责人: CAMERON F ABRAMS
• 金额: $ 11.08万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8663929
• 关键词: AQP1 gene; Carbon Monoxide; Carrier Proteins; Data; Diffusion; Disease; Engineering; Enzymes; Evaluation; Foundations; Free Energy; Kinetics; Life; Ligands; Methods; Myoglobin; Oxygen; Pathway interactions; Process; Protein Binding; Proteins; Publishing; Relative (related person); Sarcosine oxidase; Surface; System; Temperature; Therapeutic; base; molecular dynamics; molecular scale; novel strategies; reconstruction; simulation; small molecule; theories

DESCRIPTION (provided by applicant): The overall objective of this project is to use and further develop the mathematical framework of transition-path theory (TPT; W. E and E. Vanden-Eijnden, Annu. Rev. Phys. Chem. 2010 61:391-420) to quantify rates of small molecule entry/exit and intramolecular diffusion in proteins. Based on all-atom molecular dynamics, the project combines free-energy reconstruction using single sweep, pathway estimation using zero-temperature string method, determination of the committor function, and milestoning calculations with isocommittor dividing surfaces. The focus is on drawing inferences regarding rate-determining mechanisms using the committor and on using isocommittor foliation to enhance the computational efficiency of milestoning for computing exact rates. We consider three major penetrant/protein systems: (i) CO/myoglobin; (ii) O2/monomeric sarcosine oxidase (MSOX); and (iii) H2O/aquaporin-1. In each case, rate quantification will serve to evaluate the relative contribution of putative entry/exit portals and transport pathways to overall kinetics. To date, no simulation methods have been published which predict rates of ligand entry and intramolecular transport. Importantly, TPT provides the theoretical basis for computing the committor function which is used in a statistical description of reactive trajectories. The key intellectual contribution of this project will be demonstrating the computation of the committor in above important protein/ligand systems as well as using it to identify rate-limiting mechanisms and to enhance the efficiency and accuracy of milestoning for computing exact rates. However, although TPT makes committor determination conceptually straightforward, it remains so far unresolved how best to compute it and then apply it in practice in large-scale biomolecular simulations. If successful, it is anticipated that these approaches will allow for meaningful evaluation of putative transport pathways and entry/exit portals when compared to experimental kinetic data.

描述（由申请人提供）：该项目的总体目的是使用并进一步发展过渡路径理论的数学框架（TPT； W。E和E. Vanden-Eijnden，Annu。Annu。Rev。Phys。Chem。20102010 61：391-420），以量化小分子进入/出口/出口/出口/exit/Exit/Exit和protemallecular ofsemelacular in prote蛋白的速率。基于全原子分子动力学，该项目使用单个扫描，使用零温度的弦乐方法，确定委员会功能的确定途径以及使用等函数分隔表面的迈尔斯顿计算结合了自由能重建。重点是使用委员会和使用等委员会叶叶来提高对速率确定机制的推论，以提高计算精确速率的迈尔斯顿的计算效率。我们考虑三个主要的渗透/蛋白质系统：（i）CO/肌红蛋白； （ii）O2/单体肌苷氧化酶（MSOX）； （iii）H2O/Aquaporin-1。在每种情况下，费率量化都将有助于评估推定进入/出口门户和运输途径对整体动力学的相对贡献。迄今为止，尚未发布模拟方法，可以预测配体进入和分子内转运的速率。重要的是，TPT为计算反应性轨迹统计描述中使用的委员会函数提供了理论基础。该项目的关键智力贡献将是在上述重要的蛋白质/配体系统中证明委员会的计算，并使用它来识别限制速率的机制，并提高计算精确速率的Morilestoning的效率和准确性。但是，尽管TPT从概念上直接确定了委员会的确定，但到目前为止，它仍然尚未解决如何最好地计算它，然后将其应用于大规模的生物分子模拟中。如果成功的话，与实验动力学数据相比，这些方法将允许对推定的传输途径和进入/退出门户进行有意义的评估。