DFT Modeling of Steroid–Phospholipid Noncovalent Interactions: Conformations, Binding Energy, and Solvation Effects

DFT Modeling of Steroid–Phospholipid Noncovalent Interactions: Conformations, Binding Energy, and Solvation Effects

Alvin Sherman Library

Steroids (STRs) have essential roles in human physiology and disease, regulating processes such as metabolism and immunity. STRs exert their effects through receptor-mediated pathways and by modulating cell membrane properties. STRs can intercalate into phospholipid (PL) bilayers, altering membrane properties that can influence downstream biological processes. While STR-protein interactions have been widely studied, little is known about how STR-PL interactions influence membrane properties. In this study, we used density functional theory (DFT) to investigate the interactions between testosterone (TST) and cholesterol (CHOL) with three representative PLs: phosphatidylcholine (PC), phosphatidylserine (PS), and phosphatidylglycerol (PG). STR-PL complexes were modeled using an aqueous (aq) solvation model. For TST, the computed interaction energies (DE_int(aq)) were greatest when the TST hydroxyl group formed a hydrogen bond with a non-bridging phosphate oxygen (P-O_nb) of the PL headgroup rather than the fatty-acyl carbonyl oxygen (C=O). The corresponding DE_int(aq)) trend was TST-PC(P-O_nb) > TST-PS(P-O_nb) > TST-PG(P-O_nb), which is consistent with preferential stabilization of TST at the lipid-water interface. For CHOL, the DE_int(aq) trend was CHOL-PS(C=O) > CHOL-PC(P-O_nb) > CHOL-PG(C=O). In addition, for each PL class, DE_int(aq) for CHOL-PL > TST-PL. Collectively, these results indicate that STR interaction energetics depend on the PL headgroup identity, preferred hydrogen bonding sites, and the extent of contact area with the fatty acid chains. This work provides molecular-level insight into how STRs may differentially interact with PL classes and thereby influence membrane environments.