BPS2026 – Molecular simulations of proton-coupled neurotransmitter transport by VMAT2

Filling synaptic vesicles with neurotransmitters is essential in biology, as it is required for nerve signaling across a chemical synapse and for the safe storage of otherwise toxic neurotransmitters. Vesicular monoamine transporter 2 (VMAT2) uses a proton gradient to pump serotonin, dopamine, norepinephrine, and histamine into synaptic vesicles in the brain. Despite VMAT2's critical roles in biology and as a drug target, the atomic-level mechanisms by which VMAT2 performs proton-coupled neurotransmitter transport have remained unclear. To determine these mechanisms, we combine molecular simulations based on classical physics (to observe large-scale conformational transitions) with those based on quantum mechanics (to observe proton transfer reactions). This work addresses a crucial knowledge gap in basic science and informs drug discovery for neurological and neuropsychiatric disorders.