How do different hydrogen bonding schemes between different amino acids and lipid headgroups generate nanoscopic membrane curvature needed for pore formation?
At present, our simulations technology is not sufficient to arrive at an atomistic understanding of peptide-induced membrane curvature generation, which is important for processes ranging from innate immunity to drug delivery and apoptosis. We have a baseline understanding of side-chain interactions at the level of potential of mean force, but nothing at the level of a quantum mechanical calculation to inform our qualitative ideas. In this work, we investigate the physical origin of peptide-induced membrane curvature by contrasting differences between H-bonding interactions of prototypical cationic amino acids (Arg and Lys) with phosphate groups of phospholipid heads using quantum mechanical calculations of a minimum model, and test the results via synthetic transporter sequences without the geometric constraints of polypeptide backbones. We find surprises that are not predicted by simple qualitative arguments, and for the first time have atomistic insight into why some cationic amino acids generate negative Gaussian membrane curvature topologically required for membrane destabilization, while others with the same charge do not. These results suggest that it is possible to achieve deterministic molecular design of pore forming peptides.