BPS2026 – A dance between tail splay and fluidity in alcohol-altered membrane fusion: A biophysical model

Neuronal communication relies on exocytosis, the fusion of vesicles with a membrane. To further understand the lipid membrane dynamics of exocytosis, we examined how short-chain alcohols influence vesicle fusion with a planar membrane in a protein-free system. In our assay, fusion is driven by an osmotic gradient between the cis (intracellular) and trans (extracellular) chambers. Using this technique, we have quantified the fusion rates of four short-chain primary alcohols with respect to asymmetric or symmetric addition. Our previous results showed that different alcohols can either inhibit or excite fusion depending on cis or trans addition. We hypothesize that alcohols inhibit fusion by inducing fluidity in the membrane, while alcohols promote fusion by decreasing the activation energy through lipid tail splay. Lipid tail splay is thought to be the nucleating event promoting membrane fusion. To explore this hypothesis, we are developing a biophysical model of this system. The primary parameters are the concentration of alcohol within each leaflet of the planar and vesicle membranes. The model includes, for each alcohol, the partition coefficients and flip rates between leaflets. Since fusion is driven by an osmotic gradient via vesicle membrane tension, we also consider the salt concentrations in the bulk solutions and how stirring impacts both salt and alcohol concentrations near the membrane. Our multiparameter model fits most of our dataset and is consistent with our hypothesized mechanisms. In other ongoing projects, we are investigating the effects of other alcohols and volatile general anesthetics on vesicle fusion to further our understanding of exocytosis and the effects of these compounds on neurons.