Unraveling the molecular mechanisms of emergent elasticity in lipid-sterol membranes

Membrane elasticity plays critical regulatory roles in biological processes and artificial cell constructs. It dictates cellular stability and deformation, protein insertion and folding, and the activity of mechanosensitive ion channels. However, recent studies have revealed that membranes exhibit elastic properties that vary with composition and observation scales. For instance, cholesterol – a predominant component of mammalian plasma membranes – stiffens saturated lipid membranes on both nanoscopic and microscopic scales, consistent with its condensing effect. In contrast, cholesterol softens unsaturated lipid membranes on microscopic scales yet stiffens them on the nanoscale. MD simulations attribute these discrepancies to slow dynamic processes (e.g. diffusion and flip-flop) which manifest weakly on the nanoscale but could significantly alter microscopic membrane dynamics. To address this conundrum, we exploit engineered molecules formed by lipid-sterol conjugation to experimentally tune flip-flop and diffusive dynamics. By synergistically combining nanoscale neutron spin-echo studies and microscale flicker spectroscopy, we show that – unlike their cholesterol analogues – these molecules cause stiffening in unsaturated membranes on nanoscopic as well as microscopic scales. Our findings shed light on key molecular mechanisms underlying emergent physical properties of lipid membranes, with important implications in biological function and practical applications.