The transport of protons in biomolecular systems is a phenomenon of fundamental importance to processes such as ATP synthesis, enzyme catalysis, the maintenance of pH gradients, proton pumping, viral infection, and substrate/ion transport across membranes via protein transporters, symporters, and antiporters. Modeling biomolecular proton translocation in silico is a significant challenge due to the complex chemical reactions involved in Grotthuss proton shutting between water molecules and with protonatable amino acids, as well as the complexity of the target biomolecular systems. In most cases, it is not only important to understand the mechanism of proton binding and transport, but also its coupling to other mechanistically relevant biomolecular processes, such as protein conformational changes, substrate binding, other protonation events, and dynamic hydration. In this project the continued development and application of a powerful multiscale computer simulation methodology is described for the study of proton transport in several key classes of proton translocating biomolecular systems, including channels (influenza A and B M2 channels), antiporters/symporters (ClC Cl-/H+ antiporter and phosphate transporter, respectively), and transporters (proton-coupled oligopeptide transporter and EmrE multidrug transporter). The overall research plan is made possible by a novel reactive molecular dynamics simulation approach integrated with quantum mechanics/molecular mechanics (QM/MM) methods that allows for the study of explicit long-length and -time scale proton transport through water molecules and ionizable molecular groups in hydrogen-bonded networks, as well as by new innovations in enhanced free energy sampling methodology, machine learning, kinetic network theory, and coarse-graining. A primary goal in the research with this methodology in hand is to reveal the mechanisms of proton transport, as well as its coupling to hydration and conformational changes, in the above mentioned biomolecular systems. All of these studies will be carried out in collaboration with leading experimentalists, while continuing to add a new dimension to the field of biomolecular computer simulation as a whole. 1
In this project, computer simulations will be used to study proton transport in several important biomolecular systems. Proton translocation is of fundamental significance throughout biology, as demonstrated by the pH-dependence of biomolecular structure and function and the central role of transmembrane proton gradients in bioenergy conversion. Moreover, understanding proton transport is of fundamental importance and direct relevance to numerous aspects of human health, including metabolism, aging, diabetes, neurodegeneration, retinal degeneration, antivral and anti-bacterial therapeutics, and homeostasis. 1
| 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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