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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的我们的合作团队最近开发了一种称为过渡路径理论/马尔可夫迈尔斯顿（TPT/mm）的方法为了预测全原子模拟中的广义过渡速率。它的实用性在蛋白质中的小气体分子进入和退出[Yu等，J Amer Chem Soc 2015; 147：3041]。的总体目标该项目是开发TPT/MM方法来处理蛋白质的多原子配体的结合和解开涉及（a）结合位点脱位和（b）蛋白质的大规模构象变化。另外，我们的目标测试新方法，使TPT/MM更加有效。该项目涉及两名博士后研究人员和两个博士学位的学生，其中一个是两个合作机构（Drexel U.和NYU）中的每个学生。活动将涉及代码开发和大规模分子模拟，以实施（1）结合位置所需的偏置采样水合以及（2）蛋白质和配体构象变化。感兴趣的测试床系统包括ATP和底物与表皮生长因子受体激酶（EGFRK）以及底物和Inibitor结合与HIV-1蛋白酶的结合。这最终目标是一种可靠的，经过验证的方法，用于估算基于3D全原子结构的配体乘率和离率在公共数据库中可用。