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.

Public Health Relevance

This project uses conceptually novel approaches to understand fundamental, molecular-scale processes essential for life. Particular focus lies on processes in which proteins for bind, transport, and release small molecules such as oxygen and carbon monoxide. This project will provide a foundation for the eventual engineering of therapeutics against disorders involving such transporter proteins and enzymes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZGM1-CBCB-5 (BM))
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Wehrle, Janna P
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Drexel University
Engineering (All Types)
Schools of Engineering
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) A computational study of water and CO migration sites and channels inside myoglobin. J Chem Theory Comput 9:1265-1271
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
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