Free energies of lipid binding: A comparison of estimates from coarse-grained and atomistic molecular dynamics

Coarse-grained molecular dynamics simulations (CG-MD) are well-suited to the study of lipid sorting by transmembrane proteins due to the accessible time scales of lipid diffusion. Unfortunately, comparison of these results to those from atomistic simulations has not been possible due to a lack of atomistic reference data; estimating free energies of binding for flexible chains in phase-separated systems like phospholipids has been unfeasible at atomistic resolution. We have recently introduced the Streamlined Alchemical Free Energy Perturbation (SAFEP) protocol for calculating such affinities. ELIC is a member of the pentameric ligand-gated ion channel (pLGIC) protein family, which includes essential neurotransmitter receptors that directly bind lipids. Here, we calculate the absolute binding affinity of POPG to multiple conformations of the Erwinia ligand-gated ion channel (ELIC) by two methods: 1) with SAFEP and the CHARMM forcefield and 2) with lipid densities and the MARTINI forcefield. These data provide one of the first quantitative comparisons of lipid-protein binding affinities across simulation resolutions. These results also serve as a proof-of-principle to illustrate complementarity between inexpensive CG-MD and more accurate all-atom free energy methods in studying lipid-protein interactions.