How lipids modulate association of proteins in lipid membranes.

Abstract

Membrane proteins mediate most specific functions of cellular membranes, including energy conversion, selective transport of ions and nutrients, cellular recognition, and signaling. It is well established that the functional activity of membrane proteins depends on various physical and chemical parameters, among which membrane lipid composition is one of the factors that has been widely explored. As membrane proteins perform their function, they often associate with each other. At the molecular level, these protein-membrane interactions can be fine-tuned by two crucial mechanical properties of the lipid membrane: i) the membrane thickness and ii) the lipid packing, a measure of how tightly lipid tails fit against each other. Accordingly, the current project aims to quantify to what extent hydrophobic mismatch (that is, the difference between the length of the protein and the thickness of the hydrophobic core of the membrane) and lipid packing contribute to the protein association using molecular dynamics simulations. Specifically, we aim to determine sequence-independent contributions to the thermodynamics of dimer stabilization, as well as the molecular basis of the hydrophobic mismatch. We expect to find a simple, additive relationship between hydrophobic mismatch, lipid packing, and the free energy of dimer formation. To capture sequence-independent trends in protein association, we propose a simplified representation of a transmembrane helix. Our model will allow controlling the extent of the hydrophobic mismatch simply by changing the length of the helix model and adjusting parameters such as particle diameter or surface roughness to mimic other biological peptides.