Transition Path Theory and Markovian Milestoning for Prediction of Protein-Ligand Binding Kinetics in Molecular Simulations

分子模拟中蛋白质-配体结合动力学预测的转变路径理论和马尔可夫里程碑

• 批准号: 9239595
• 负责人: CAMERON F ABRAMS
• 金额: $ 40.31万
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9239595
• 关键词: Affinity; Algorithms; Attention; Beds; Binding; Binding Proteins; Binding Sites; Biological Process; Biology; Code; Complex; Databases; Development; Dimensions; Doctor of Philosophy; Drug Design; Drug Targeting; Epidermal Growth Factor Receptor; Event; Formulation; Free Energy; Gases; Globin; Goals; HIV-1 protease; Hydration status; Hydrogen Bonding; Ice; Institution; Kinetics; Ligands; Measures; Methods; Modeling; Molecular; Molecular Conformation; Molecular Structure; Mutation; Occupations; Pathway interactions; Pensions; Peptides; Pharmaceutical Preparations; Phosphotransferases; Process; Protein Conformation; Proteins; Reaction; Research Personnel; Role; Sampling; Sampling Biases; Slave; Speed; Structure; Students; Surface; Surgical Flaps; System; Temperature; Testing; Time; Water; Work; base; clinically relevant; flexibility; inhibitor/antagonist; innovation; interest; molecular dynamics; molecular scale; mutant; novel strategies; simulation; solute; theories

ABSTRACT Our collaborative team recently developed a method termed Transition-Path Theory/Markovian Milestoning (TPT/MM) for the prediction of generalized transition rates in all-atom simulations. Its utility was demonstrated in the context of small gas molecule entry and exit in proteins [Yu et al., J Amer Chem Soc 2015;147:3041]. The overarching objective of this project is to develop the TPT/MM approach to handle the binding and unbinding of polyatomic ligands from proteins which involve (a) binding site desolvation and (b) large-scale conformational changes of the protein. Additionally we aim to test new approaches to making TPT/MM even more effiecient. The project involves two postdoctoral researchers and two PhD students, one of each at each of the two collaborating institutions (Drexel U. and NYU). Activities will involve code development and large-scale molecular simulations to implement the required biased sampling of (1) binding-site hydration and (2) protein and ligand conformational changes. Test-bed systems of interest include ATP and substrate binding to epidermal growth factor receptor kinase (EGFRK), and substrate and inibitor binding to HIV-1 protease. The ultimate goal is a robust, validated method for estimating ligand on- and off-rates based on 3D all-atom structures available in public databases.

摘要 我们的合作团队最近开发了一种称为转移路径理论/马尔可夫里程碑（TPT/MM）的方法 用于全原子模拟中广义跃迁速率的预测。它的实用性在以下方面得到了证明： 小气体分子进入和离开蛋白质[Yu等，J Amer Chem Soc 2015;147：3041]。的总体目标 这个项目是开发TPT/MM方法来处理蛋白质上多原子配体的结合和解结合 其涉及（a）结合位点去溶剂化和（B）蛋白质的大规模构象变化。此外，我们旨在 测试使TPT/MM更有效的新方法。该项目涉及两名博士后研究人员， 两名博士生，分别来自两个合作机构（德雷克塞尔大学）。NYU）。活动将涉及 代码开发和大规模分子模拟，以实现（1）结合位点所需的偏置采样 水化和（2）蛋白质和配体构象变化。感兴趣的试验台系统包括ATP和底物 与表皮生长因子受体激酶（EGFRK）结合，以及与HIV-1蛋白酶结合的底物和抑制剂。的 最终的目标是一个强大的，验证方法估计配体上和关闭率的基础上三维全原子结构 在公共数据库中。