Proteins involved in cellular signaling and regulation transiently bind other proteins to propagate a signal, thereby forming an intricate network of protein-protein interaction (PPIs). In intracellular communication, these processes are initiated at the membrane surface. In fact, a significant portion of proteins in the cell are membrane-associated, accounting for as much as 30% of all genomic sequences. In addition, their lipidic environment plays a role that is to-date poorly understood. Most commonly reduced to PPIs, the interactome comprises the ensemble of molecular interactions in the cell. Other interactions, such as those with nucleic acids, lipids, carbohydrates and ions, cannot be ignored in the study of biological structure and function.
Protein-lipid interactions (PLIs) are increasingly recognized as central to the structure and function of membrane proteins. However, with the exception of simplified models, specific PLIs are particularly difficult to highlight experimentally. We have used molecular modeling and dynamics to investigate and characterize the existence of lipid-mediated salt bridges in LacY embedded in five different lipid matrices. LacY is a paradigm for the Major Facilitator Superfamily (MFS) that represents as much as 25% of all membrane transport proteins, with over 15.000 sequence members identified to date. The results have high significance ; it is the first computational study ever to highlight a specific PLI, showing unambiguously a persistent interaction between a PE lipid and conserved residues of the protein. In addition, the study has led to significant biological insight into the action of membrane transport proteins.