The focus of my research is to understand the molecular mechanisms by which different factors, such as membrane lipids, ligands and mutations, modulate the structure, dynamics and function of rhodopsin, the G protein-coupled receptor that mediates scotopic vision.
Lipid effects on rhodopsin
Using microsecond-scale all-atom molecular dynamics simulations we have studied the effect of membrane lipids on rhodopsin along its photocycle. Our work suggest that phospholipids alter rhodopsin’s structure and dynamics via both ligand-like and bulk-like effects.
GPCR activation has remained elusive for standard simulation techniques due to its intrinsic timescales. We have implemented simple models (Go models) to try to bridge this gap. In these structure-based models, only native-like interactions are present, thus producing smoothed energy landscapes by construction where water and membrane interactions are implicitly accounted for. We are currently using this approach as a platform to study rhodopsin activation/deactivation, state interconversion in equilibrium and functionally relevant point-mutations.
Ultra-fast activation dynamics
We are using well-equilibrated all-atom molecular dynamics simulations of dark state rhodopsin to aid the interpretation of time-resolved solution X-ray scattering experiments with free-electron lasers. This project is a collaborative effort with the Brown Lab, Tom Grant , Richard Kirian, Nadia Zatsepin and Derek Mendez from the BioXFEL Science and Technology Center, the Singharoy Lab and the Fromme Lab.
- Humberto Reyes-Pardo, Angel A. Barbosa-Camacho, Ana E. Pérez-Mejía, Bárbara Lara-Chacón, Leslie A. Salas-Estrada, Angélica Y. Robledo-Rivera, Gabriela M. Montero-Morán, Samuel Lara-González, Mónica R. Calera, and Roberto Sánchez-Olea. A nuclear export sequence in GPN-loop GTPase 1, an essential protein for nuclear targeting of RNA polymerase II, is necessary and sufficient for nuclear export. Biochim Biophys Acta, 1823(10): 1756–1766, 2012.
- Leslie A. Salas-Estrada, Nicholas Leioatts, Tod D Romo, and Alan Grossfield. Lipids alter rhodopsin function via ligand-like and solvent-like interactions. Biophysical Journal, 114:355–367, January 2018.
- Louis G. Smith, Aleksander Spasic, Debapratim Dutta, Leslie A Salas-Estrada, Alan Grossfield, and David H. Mathews. Chemically Accurate Relative Folding Stability of RNA Hairpins from Molecular Simulations. Journal of Chemical Theory and Computation, In Press. BioRxiv.
Department of Biochemistry and Biophysics
University of Rochester, Medical Center, Box 712
Rochester, NY 14642