Phospholipid Saturation Modulates Cholesterol Partitioning and Heat Transport in Lipid Bilayers under Thermal Gradients.

Lipid compositional asymmetry across the two leaflets of the bilayer is a defining feature of biological membranes, critically influencing their chemical and physical properties. Understanding the factors that modulate this asymmetry is essential for elucidating the mechanisms that regulate membrane and membrane protein function. Experimental evidence has demonstrated heat generation within cells, and localized heating strategies are increasingly used in thermal therapies for cancer. Additionally, electroporation techniques, which use electric pulses to make membranes permeable, can also create thermal gradients. These findings highlight the importance of understanding membrane behavior under nonequilibrium conditions. Here, we employ nonequilibrium molecular dynamics simulations with the coarse-grained MARTINI 3 force field to investigate cholesterol partitioning in lipid bilayers under thermal gradients. We explore bilayers with varying degrees of lipid saturation and cholesterol content. Our results reveal that cholesterol exhibits thermophobic behavior, preferentially accumulating in colder regions of the bilayer, a trend that aligns with previous atomistic simulations. This thermophobicity is most pronounced in bilayers composed of saturated lipids and at low cholesterol mole fractions. We further show that bilayer thermal conductivity decreases with increasing cholesterol content, while saturated phospholipid bilayers exhibit higher thermal conductance than their unsaturated counterparts. Our findings indicate that lipid composition and cholesterol levels together modulate both mass and thermal transport in lipid membranes exposed to thermal stress.