Flexible Tail of Antimicrobial Peptide PGLa Facilitates Water Pore Formation in Membranes

PGLa, an antimicrobial peptide (AMP), primarily exerts
its antibacterial
effects by disrupting bacterial cell membrane integrity. Previous
theoretical studies mainly focused on the binding mechanism of PGLa
with membranes, while the mechanism of water pore formation induced
by PGLa peptides, especially the role of structural flexibility in
the process, remains unclear. In this study, using all-atom simulations,
we investigated the entire process of membrane deformation caused
by the interaction of PGLa with an anionic cell membrane composed
of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol
(DMPG). Using a deep learning-based key intermediate identification
algorithm, we found that the C-terminal tail plays a crucial role
for PGLa insertion into the membrane, and that with its assistance,
a variety of water pores formed inside the membrane. Mutation of the
tail residues revealed that, in addition to electrostatic and hydrophobic
interactions, the flexibility of the tail residues is crucial for
peptide insertion and pore formation. The full extension of these
flexible residues enhances peptide–peptide and peptide–membrane
interactions, guiding the transmembrane movement of PGLa and the aggregation
of PGLa monomers within the membrane, ultimately leading to the formation
of water-filled pores in the membrane. Overall, this study provides
a deep understanding of the transmembrane mechanism of PGLa and similar
AMPs, particularly elucidating for the first time the importance of
C-terminal flexibility in both insertion and oligomerization processes.