Intricate Role of Cholesterol in Membrane Fusion

Cholesterol, having diverse effects in membrane deformation, can either promote or inhibit membrane fusion, as suggested by many experimental studies of protein-mediated fusion. Here, we examine the energetics of fusion intermediates and find that cholesterol modulates the fusion energy landscape in a nonmonotonic manner, facilitating the early stage of membrane fusion (stalk formation) while opposing fusion pore expansion through increased membrane bending rigidity. Furthermore, we investigate the role of proteins in modulating the energetics of these intermediates in the presence of cholesterol. Our findings reveal that symmetric transmembrane proteins, such as the transmembrane domains of t-SNARE and v-SNARE, do not significantly influence fusion energetics, consistent with their limited capacity to induce membrane curvature. In contrast, curvature-generating proteins, such as the gp41 fusion peptide, substantially reduce the free-energy barriers associated with the fusion process.