The translocation of protons in biomolecular systems is a phenomenon of fundamental importance to such biological processes as ATP synthesis, enzyme catalysis, the maintenance of pH gradients, proton pumping, and bioenergetics. From the computational point of view the modeling of proton translocation represents a particularly difficult challenge most notably because of the many complex interactions involved, the fact that bonding topologies are continually evolving due to the Grotthuss proton shutting between water molecules and also possibly with other molecular groups, the interplay of charge migration via proton shuttling and classical ion diffusion, and the overall structural complexity of the target biomolecular systems. In most instances, the primary question is the way in which Nature utilizes the proton shuttling characteristics of hydrogen bonded water chains within proteins, as well as how specific molecular groups within the protein participate in the proton translocation process via electrostatic interactions and possibly even via direct participation in the proton shuttling mechanism itself. In this project the continued development and application of a unique and powerful computer simulation methodology is described for the study of proton translocation in several key classes of proton translocating biomolecular systems, including channels (M2 proton channels of influenza A and B, mutated aquaporin channels, and chloride/proton antiporter channels), enzymes (carbonic anhydrase), and proton pumps (cytochrome c oxidase). The overall research plan is made possible by a novel Molecular Dynamics simulation approach that allows for the study of explicit proton transport through water molecules and ionizable molecular groups in hydrogen bonded networks. A primary target in the research will be to reveal the underlying microscopic biomolecular interactions which influence proton translocation in the above mentioned systems, as well as the way in which structural and chemical modifications of the proteins can affect this important property. These studies will be carried out in collaboration with several key experimentalists, while adding a new dimension to the field of biomolecular computer simulation as a whole. 1The project concerns computer simulation studies of proton translocation in several key biomolecular systems. Proton translocation is important to understanding numerous aspects of human health, including influenza viral replication, neurodegeneration, glaucoma, metabolism, and aging.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
7R01GM053148-15
Application #
7753194
Study Section
Special Emphasis Panel (ZRG1-MSFD-N (01))
Program Officer
Preusch, Peter C
Project Start
1996-05-01
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
15
Fiscal Year
2010
Total Cost
$292,664
Indirect Cost
Name
University of Chicago
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Parker, Joanne L; Li, Chenghan; Brinth, Allete et al. (2017) Proton movement and coupling in the POT family of peptide transporters. Proc Natl Acad Sci U S A 114:13182-13187
Arntsen, Christopher; Chen, Chen; Voth, Gregory A (2017) Reactive molecular dynamics models from ab initio molecular dynamics data using relative entropy minimization. Chem Phys Lett 683:573-578
Liang, Ruibin; Swanson, Jessica M J; Wikström, Mårten et al. (2017) Understanding the essential proton-pumping kinetic gates and decoupling mutations in cytochrome c oxidase. Proc Natl Acad Sci U S A 114:5924-5929
Liang, Ruibin; Swanson, Jessica M J; Peng, Yuxing et al. (2016) Multiscale simulations reveal key features of the proton-pumping mechanism in cytochrome c oxidase. Proc Natl Acad Sci U S A 113:7420-5
Lee, Sangyun; Mayes, Heather B; Swanson, Jessica M J et al. (2016) The Origin of Coupled Chloride and Proton Transport in a Cl(-)/H(+) Antiporter. J Am Chem Soc 138:14923-14930
Lee, Sangyun; Liang, Ruibin; Voth, Gregory A et al. (2016) Computationally Efficient Multiscale Reactive Molecular Dynamics to Describe Amino Acid Deprotonation in Proteins. J Chem Theory Comput 12:879-91
Lee, Sangyun; Swanson, Jessica M J; Voth, Gregory A (2016) Multiscale Simulations Reveal Key Aspects of the Proton Transport Mechanism in the ClC-ec1 Antiporter. Biophys J 110:1334-45
Taraphder, Srabani; Maupin, C Mark; Swanson, Jessica M J et al. (2016) Coupling Protein Dynamics with Proton Transport in Human Carbonic Anhydrase II. J Phys Chem B 120:8389-404
Liang, Ruibin; Swanson, Jessica M J; Madsen, Jesper J et al. (2016) Acid activation mechanism of the influenza A M2 proton channel. Proc Natl Acad Sci U S A :
Dama, James F; Hocky, Glen M; Sun, Rui et al. (2015) Exploring Valleys without Climbing Every Peak: More Efficient and Forgiving Metabasin Metadynamics via Robust On-the-Fly Bias Domain Restriction. J Chem Theory Comput 11:5638-50

Showing the most recent 10 out of 54 publications