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 ef?ecient. 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.

Public Health Relevance

We propose to develop a method to compute on- and off-rates of drug-like molecules to protein targets based on all-atom molecular dynamics simulations and transition-path theory. If successful, this method could be very useful in computationally evaluating effects of drug designs and target mutations on binding kinetics, providing a new basis upon which to optimize drug molecule structure. It may also be helpful in understanding the role of intermolecular kinetics on biology in general.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function D Study Section (MSFD)
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Lyster, Peter
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Drexel University
Engineering (All Types)
Biomed Engr/Col Engr/Engr Sta
United States
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Bucci, Anthony; Yu, Tang-Qing; Vanden-Eijnden, Eric et al. (2016) Kinetics of O2 Entry and Exit in Monomeric Sarcosine Oxidase via Markovian Milestoning Molecular Dynamics. J Chem Theory Comput 12:2964-72
Wu, Xiongwu; Brooks, Bernard R; Vanden-Eijnden, Eric (2016) Self-guided Langevin dynamics via generalized Langevin equation. J Comput Chem 37:595-601
Yu, Tang-Qing; Lu, Jianfeng; Abrams, Cameron F et al. (2016) Multiscale implementation of infinite-swap replica exchange molecular dynamics. Proc Natl Acad Sci U S A 113:11744-11749
Yu, Tang-Qing; Lapelosa, Mauro; Vanden-Eijnden, Eric et al. (2015) Full kinetics of CO entry, internal diffusion, and exit in myoglobin from transition-path theory simulations. J Am Chem Soc 137:3041-50
Maragliano, Luca; Roux, BenoƮt; Vanden-Eijnden, Eric (2014) Comparison between Mean Forces and Swarms-of-Trajectories String Methods. J Chem Theory Comput 10:524-33
Yu, Tang-Qing; Chen, Pei-Yang; Chen, Ming et al. (2014) Order-parameter-aided temperature-accelerated sampling for the exploration of crystal polymorphism and solid-liquid phase transitions. J Chem Phys 140:214109
Bucci, Anthony; Abrams, Cameron F (2014) Oxygen Pathways and Allostery in Monomeric Sarcosine Oxidase via Single-Sweep Free-Energy Reconstruction. J Chem Theory Comput 10:2668-2676
Lapelosa, Mauro; Abrams, Cameron F (2013) Transition-Path Theory Calculations on Non-Uniform Meshes in Two and Three Dimensions using Finite Elements. Comput Phys Commun 184:2310-2315
Lapelosa, Mauro; Abrams, Cameron F (2013) A computational study of water and CO migration sites and channels inside myoglobin. J Chem Theory Comput 9:1265-1271
Stober, Spencer T; Abrams, Cameron F (2012) Energetics and mechanism of the normal-to-amyloidogenic isomerization of ?2-microglobulin: on-the-fly string method calculations. J Phys Chem B 116:9371-5