Functional Lipid−Protein Interactions in Integral Membrane Proteins

ended

Membrane proteins constitute a third of the human proteome and their relevance to disease has led these proteins to make up more than half of all current drug targets. However, despite this push to identify agents for membrane proteins, the number of established disease-associated targets are limited. The 'open' and solvent-accessible nature of most membrane protein orthosteric sites often results in limited specificity of potential drugs. The Trans-Membrane domains (TMD) while displaying greater variability among membrane proteins were however long considered lacking in specific interactions. But significant developments in experimental techniques are now identifying this domain to interact and be actively regulated by the diverse lipid components of the membrane. This Lipopeutics project attempts to determine if the analysis of the protein's Lipid interactions can be a pathway to the development of allosteric drugs targeted at these bilayer-exposed pockets. Unfolding in three major steps, the project first aims to identify specific lipid binding sites with the TMD through the use of long-timescale coarse-grain Molecular Dynamics simulations. Subsequently, the role of this lipid binding event in the protein's functional modulation is validated through atomistic simulations using the Markov State Modelling approach. Finally, cheminformatic screening is used to design lipid-mimicking compounds that are capable of binding within the hydrophobic pocket and stabilizing specific protein functional states.