Utilizing the Geometrical Route to Analyze Peripheral Membrane-Binding Proteins

Current: Stephen Gee
Collaborators: Benoît Roux, Christophe Chipot

The geometrical route is a technique for calculating binding free energies from molecular dynamics simulations. It involves the restraining of geometrical degrees of freedom of the system as the ligand is pulled away from its binding site. Although it has been proven to yield accurate results for binding in solution (Fu, 2023) and within membranes (Blazhynska, 2023), the geometrical route has yet to be applied to peripheral membrane-binding protein systems. We aim to validate the geometrical route for the simplest of such systems and expand it to apply to more complicated proteins. Ultimately, we hope to generate a protocol for calculating the binding free energies of peripheral membrane-binding proteins, including those with ion-dependencies, multiple binding sites, and other complexities.

Selected bibliography

Fu, H., Chen, H., Blazhynska, M. et al. Accurate determination of protein:ligand standard binding free energies from molecular dynamics simulations. Nat Protoc 17, 1114–1141 (2022). https://doi.org/10.1038/s41596-021-00676-1
Haohao Fu, Christophe Chipot, Xueguang Shao, and Wensheng Cai, Journal of Chemical Information and Modeling 2023 63 (8), 2512-2519. https://doi.org/10.1021/acs.jcim.3c00487
James C. Gumbart, Benoît Roux, and Christophe Chipot, Journal of Chemical Theory and Computation 2013 9 (1), 794-802. https://doi.org/10.1021/ct3008099
Marharyta Blazhynska, James C. Gumbart, Haochuan Chen, Emad Tajkhorshid, Benoît Roux, and Christophe Chipot, Journal of Chemical Theory and Computation 2023 19 (24), 9077-9092. https://doi.org/10.1021/acs.jctc.3c00941