BPS2026 – Distinct interactions of dopamine and L-DOPA with complex lipid membranes revealed by NMR and MD simulations

Dopamine and its precursor L-DOPA play central roles in neurotransmission and have been implicated in Parkinson’s disease and other neurological disorders. In our previous work, we quantified dopamine-lipid interactions in simple bilayers composed of phosphatidylcholine (PC) and phosphatidylserine (PS) using one-dimensional NMR. Here, we extend this investigation by focusing exclusively on dopamine and L-DOPA and by broadening the lipid environment to include mixtures that more closely mimic the complexity of cellular membranes. Using 2D-NOESY NMR spectroscopy, we resolve aromatic and electrostatic contacts of dopamine with lipid headgroups and compare these with the weaker, more transient interactions of L-DOPA. Complementary molecular dynamics (MD) simulations reveal differences in orientation, hydrogen bonding, and depth of insertion across varied lipid compositions. Together, these results update and expand our earlier findings, demonstrating that lipid diversity strongly modulates catecholamine-membrane interactions, with potential implications for neurotransmitter compartmentalization and accessibility in neuronal membranes.