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 shuttling between water molecules and also possibly by amino acids, 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 proteins utilize the proton shuttling characteristics of hydrogen bonded water chains, as well as how specific molecular groups within the protein participate in the proton translocation process via electrostatic interactions and possibly even through direct participation in the proton shuttling mechanism itself. In this project the continued development and application of a unique and powerful multiscale computer simulation methodology is described for the study of proton transport in several key classes of proton translocating biomolecular systems, including pumps (cytochrome c oxidase) enzymes (carbonic anhydrase), channels (M2 proton channels of influenza A and B), and antiporters (ClC chloride/proton antiporters). The overall research plan is made possible by a novel reactive Molecular Dynamics simulation approach that allows for the study of explicit long range proton transport through water molecules and ionizable molecular groups in hydrogen bonded networks, as well as by new innovations in enhanced free energy sampling methods, coarse-graining, and kinetic network theory. 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 a number of leading experimentalists, while adding a new dimension to the field of biomolecular computer simulation as a whole. 1

Public Health Relevance

The project concerns computer simulation studies of proton translocation in several key biomolecular systems. Proton translocation is of fundamental significance in biology and important to understanding numerous aspects of human health, including influenza virus replication, neurodegeneration, glaucoma, metabolism, aging, and anti-bacterial therapeutics. 1

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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Preusch, Peter
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University of Chicago
Schools of Arts and Sciences
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Mayes, Heather B; Lee, Sangyun; White, Andrew D et al. (2018) Multiscale Kinetic Modeling Reveals an Ensemble of Cl-/H+ Exchange Pathways in ClC-ec1 Antiporter. J Am Chem Soc 140:1793-1804
Madsen, Jesper J; Sinitskiy, Anton V; Li, Jianing et al. (2017) Highly Coarse-Grained Representations of Transmembrane Proteins. J Chem Theory Comput 13:935-944
Sun, Rui; Sode, Olaseni; Dama, James F et al. (2017) Simulating Protein Mediated Hydrolysis of ATP and Other Nucleoside Triphosphates by Combining QM/MM Molecular Dynamics with Advances in Metadynamics. J Chem Theory Comput 13:2332-2341
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
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
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
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
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 113:E6955-E6964
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

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