Approaches to computing diffusion rates in proteins from transition path theory

描述（由申请人提供）：本项目的总体目标是使用和进一步发展过渡路径理论（TPT; W。E和E。范登-艾因登2010 61：391-420）来定量蛋白质中小分子进入/离开和分子内扩散的速率。基于全原子分子动力学，该项目结合了使用单扫描的自由能重建，使用零温弦方法的路径估计，确定commitor函数，以及使用isocommitor划分表面的里程碑式计算。重点是利用提交者和使用isocommittor叶状来提高里程碑计算精确速率的计算效率，从而得出关于速率确定机制的推论。我们考虑三个主要的渗透剂/蛋白质系统：（i）CO/肌红蛋白;（ii）O2/单体肌氨酸氧化酶（MSOX）;和（iii）H2O/水通道蛋白-1。在每种情况下，速率定量将用于评价推定的进入/退出门户和转运途径对总体动力学的相对贡献。迄今为止，没有模拟方法已公布的配体进入和分子内运输的预测率。重要的是，TPT提供了理论基础，用于计算的提交函数，这是用于统计描述的反应轨迹。该项目的主要智力贡献将是展示上述重要蛋白质/配体系统中提交者的计算，以及使用它来识别限速机制，并提高计算精确速率的里程碑的效率和准确性。然而，尽管TPT使提交者确定在概念上简单明了，但到目前为止仍然没有解决如何最好地计算它，然后将其应用于大规模生物分子模拟的实践中。如果成功，预计这些方法将允许有意义的评估推定的运输途径和入口/出口门户相比，实验动力学数据。

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.