BPS2026 – Dynamics of lipid-anchored membrane proteins

We have shown previously that the catalytic domain of lipid-modified small GTPases dynamically interacts with lipids. An intriguing implication of this observation was the possibility of exploiting these transient interactions for therapeutic purposes. Here, we show that these exit ligands whose binding affinity is substantially greater when the GTPase is in lipid nanodiscs than in isolation. Molecular dynamics simulations suggest that the ligands either simultaneously interact with lipids and protein residues or stabilize the complex allosterically. The broader implication of these findings for developing therapeutic agents targeting membrane-bound small GTPases will be discussed.