TRPA1, a member of the transient receptor potential (TRP) ion channel superfamily, is a nonspecific cation channel activated by natural chemicals found in, for instance, mustard, oregano, and cinnamon. TRPA1 has recently appeared as a promising drug target in pain and inflammatory diseases. Structure-based design efforts for this protein are problematic, however, due to the lack of molecular details of relevant channel functional states and of channel activation.
To address this problem, we have studied TRPA1 channel functional states and channel activation using long-timescale, all-atom molecular dynamics simulations enabled by special-purpose hardware. Specifically, we simulated inward and outward ionic currents, which helped us identify possible key structural determinants of channel gating. We also studied modulation of the open and conducting channel by performing simulations of free binding of the TRPA1 inhibitor A-967079 to TRPA1. Intriguingly, A-967079 was observed to bind in a location previously hypothesized to be a binding site. Our observations suggest that this site may indeed be a target for development of new allosteric modulators, an avenue we intend to explore in the future.
Heidi Koldsø is a member of the technical team at D. E. Shaw Research, a company that develops specialized hardware and software for basic and applied computational biochemical research. She holds a Ph.D. in chemistry from Aarhus University in Denmark, as well as a M.Sc. and B.Sc. in Medicinal Chemistry, also from Aarhus University. After her Ph.D., she was a postdoctoral researcher at the Department of Biochemistry, University of Oxford. At D. E. Shaw Research, she applies molecular dynamics simulations to study biological systems, with a focus on ion channels.
Heidi Koldsø is a member of the technical team at D. E. Shaw Research, a company that develops specialized hardware and software for basic and applied computational biochemical research. She holds a Ph.D. in chemistry from Aarhus University in Denmark, as well as a M.Sc. and B.Sc. in Medicinal Chemistry, also from Aarhus University. After her Ph.D., she was a postdoctoral researcher at the Department of Biochemistry, University of Oxford. At D. E. Shaw Research, she applies molecular dynamics simulations to study biological systems, with a focus on ion channels.
BAGIM is sponsored by Dassault Systemes, DNASTAR, LabAnswer, OpenEye Scientific, Schrodinger, Silicon Therapeutics, Acellera, Acpharis, Cambridge Crystallographic Data Centre, Chemical Computing Group, Dotmatics, Cresset, Cyrus Biotechnology, Optibrium, Team Arrayo, and Scilligence
