Estimating mutual influence in protein-membrane systems for receptor tyrosine kinases in computer experiments
National Research University Higher School of Economics, Myasnitskaya Str., 20, Moscow, 101000, Russia. M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry RAS, Miklukho-Maklaya Str., 16/10, Moscow, GSP-7, 117997, Russia; +7(495)330-58-74, email@example.com
Receptor tyrosine kinases form an important class of membrane proteins that regulate cell life cycle and metabolism. Among wide variety of receptors, they have simple structure with single alpha-helix crossing the membrane. This transmembrane domain is functionalm as dimeric state conformation defines active/inactive state of the receptor. The lipid environment can modulate functioning of such proteins, but the exact details are not well described yet . In addition to specific interactions with certain types of lipids, cholesterol and gangliosides, there are non-specific ones, since physico-chemical parameters are dependent on local lipid composition around protein molecule. However, there are opposite hypotheses about what is the driving force of heterogeneities formation in the membrane: lipid molecules themselves or membrane proteins embedded in the bilayer. To answer the question on mutual influence of proteins and their lipid environment, we used atomistic computer modeling: molecular dynamics simulations followed by a detailed analysis of intermolecular contacts to identify key amino acid residues that determine protein-lipid interactions. It was shown that the number of protein-lipid contacts depends on the conformation of the dimeric state, and their distribution over the monolayers is asymmetric. The results of the work will help in understanding the mechanism of signal transduction by receptor tyrosine kinases and finding ways to influence their activity.