Abstract
The human StAR-related lipid transfer domain protein 2 (STARD2), also known as phosphatidylcholine (PC) transfer protein, is a single-domain lipid transfer protein thought to transfer PC lipids between intracellular membranes. We performed extensive μs-long molecular dynamics simulations of STARD2 of its apo and holo forms in the presence or absence of complex lipid bilayers. The simulations in water reveal ligand-dependent conformational changes. In the 2 μs-long simulations of apo STARD2 in the presence of a lipid bilayer, we observed spontaneous reproducible PC lipid uptake into the protein hydrophobic cavity. We propose that the lipid extraction mechanism involves one to two metastable states stabilized by choline-tyrosine or choline-tryptophane cation-π interactions. Using free energy perturbation, we evaluate that PC-tyrosine cation-π interactions contribute 1.8 and 2.5 kcal/mol to the affinity of a PC-STARD2 metastable state, thus potentially providing a significant decrease of the energy barrier required for lipid desorption.