Peptide Sequence Features that Reduce Membrane Pore Line Tension

Membrane pore stability is central to many processes involving membrane permeabilization, yet it remains unclear how the sequence of pore-localizing peptides can modify the energetics of the pore boundary. For large pores, the energetic cost associated with increasing pore size is described by the membrane line tension. Peptides capable of reducing line tension can therefore stabilize permeable membrane states, making their identification relevant for the design of membrane-active molecules. Here, we combine coarse-grained molecular dynamics simulations, free energy calculations, and evolutionary optimization algorithms to identify sequence features of -helical peptides that reduce membrane line tension. The best-performing peptides consistently showed an amphipathic organization with aromatic-rich termini, a hydrophobic/aromatic membrane-facing nonpolar face, and a negatively charged polar face. These sequence features promoted peptide localization at the pore rim close to the intact bilayer and orientation parallel to the membrane edge. This binding geometry reorganized lipids at the pore rim and efficiently reduced the exposure of their hydrophobic tails to water, thereby reducing the energetic cost of the pore boundary. The main sequence and mechanistic trends identified in coarse-grained simulations were reproduced in all-atom simulations. Together, these results link peptide sequence to pore-rim localization, lipid reorganization, and ultimately line-tension reduction, providing molecular design principles for $\alpha$-helical peptides that stabilize permeable membrane states.