Membrane-binding mechanism of a peripheral membrane protein through microsecond molecular dynamics simulations.

A homologue oxysterol binding protein of yeast (Osh4) peripherally binds to organelle and plasma membranes and promotes lipid transport and membrane contact. Extensive molecular dynamics simulations of Osh4 are used to characterize the structure and mechanism of protein attachment to various model lipid membranes. A high density of negatively charged lipids (phosphatidylserine and phosphatidylinositol-4,5-biphosphate) or a low density of phosphatidylinositol-4,5-biphosphate results in a single binding conformation consisting of interactions with several loops and a portion of the mouth to the lipid binding pocket. However, Osh4 weakly and transiently binds to membranes with only zwitterionic lipids. The protein conformation in our simulations with anionic membranes agrees with previous experiments but offers an alternative description to previously proposed distinct binding regions. Specifically, distinct binding sites on Osh4 also constitute a single binding conformation with anionic membranes. Several loops interact strongly with membranes with the strongest being the β14-β15 loop (amino acids 253-264), but this loop binds in a nonspecific manner to any anionic lipid. We are the first to characterize the importance of an anchor in the phenylalanine loop (amino acids 236-244) to binding, which stabilizes distant interactions with the mouth and may be important in stabilizing mouth interactions for lipid release or uptake to or from membranes.