On the effect of lateral stretch on the deformation energetics of biological membranes and the lipid dynamics within

Abstract A broad range of cellular functions involve transient or persistent changes in the morphology of lipid membranes, from the organellar to the molecular scale. By and large, the thermodynamics of these remodeling processes remain to be understood. Molecular Dynamics simulations enhanced by advanced sampling methods are uniquely suited to examine and quantitate these phenomena. Here, we focus on the cellular process known as mechanosensation and use the Multi-Map simulation method to quantify how applied lateral tension impacts the energetics of both global and localized membrane perturbations induced extrinsically. We also examine how tension impacts the dynamics of lipid molecules. We find that the conformational energetics of the membrane clearly differs when it is stretched, and that this difference increases with the magnitude of the applied tension. The reason is not that tension alters the mechanical properties of the lipid bilayer, such as its bending modulus, but rather that it opposes any reduction in the projected area of the membrane relative to that at rest, while the opposite is favored. It follows that tension may shift a conformational equilibrium of a protein that deforms the membrane differently in alternative functional states, if that difference also entails a change in the projected membrane area. Conversely, we find that stretch has little to no effect on the dynamics of lipids at the single-molecule level, implying it would also have no bearing on the lifetime of specific protein-lipid interactions. Finally, we show how changes in lipid composition that result in global membrane thinning can mimic the effect of lateral stretch without any applied tension. Statement of Significance Cells have evolved the ability to sense mechanical forces, such as pressure or stretch, through specialized proteins embedded in their membranes. How exactly the membrane transduces these stimuli to the proteins therein has been unclear. Using state-of-the-art computer simulations, we show that stretching a membrane does not result in forces that pull or push on the individual lipid molecules that constitute the membrane. Instead, lateral tension alters the energetics of reshaping the membrane. This shift in plasticity explains why several well-known force-sensing proteins switch between active and inactive states at specific tension values observed experimentally. We also show that altering the lipid composition of the membrane can produce the same effect as lateral stretch, without any applied force. Competing Interest Statement The authors have declared no competing interest.