Computational insights into the lipid code of transient receptor potential vanilloid channels reveal overlap with drug binding sites

In this study, we characterize the plasma membrane paralipidome of the entire TRPV subfamily using microsecond coarse-grained molecular dynamics (CG-MD) simulations. We describe the lipids in the immediate protein environment, identify lipid binding regions, and map the nature of the binding sites. Key lipid interactions include cholesterol, phosphatidylinositols, phosphatidylserine, and phosphatidylethanolamine. Cholesterol shows preferential and stable binding driven by hydrophobicity to specific and conserved regions in the transmembrane domain. Phosphatidylinositols are located in polybasic patches close to the cytosolic side of the bilayer. Our findings reveal long-lasting specific interactions in previously described binding sites, but also novel lipid pockets, mapped by residue type and conservation. Our approach confirms known and uncovers new bioactive lipid binding sites, and through deeper analysis, we show lipids overlapping with drug-binding sites, which may open opportunities for lipid-based therapies and drug discovery in membrane proteins.