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Charged Antimicrobial Peptides Can Translocate across Membranes without Forming Channel-like Pores.
Ulmschneider JP
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How can highly charged, cationic antimicrobial peptides (AMPs) translocate across hydrophobic lipid bilayers despite the prohibitive energetic penalty to do so? A common explanation has been the formation of peptide-lined channels. However, for most AMPs, no structures of membrane pores have been found despite clear evidence of membrane leakage and antimicrobial activity. The study here suggests an alternative and simple reason: for the AMP PGLa from Xenopus laevis (charge +5), such pores are not needed to explain both leakage and peptide translocation. Elevated-temperature multimicrosecond equilibrium simulations at all-atomistic level reveal that peptides spontaneously translocate across the membrane individually on a timescale of tens of microseconds, without forming pores. Both surface-bound peptides and lipids assist in the one-by-one translocation of the charged side chains. Single peptides can remain in a transmembrane orientation for many microseconds, snorkeling some charged residues to one interface and some to the opposite, but without inducing a water channel. Instead of stable pores, short-lived water bridges occur when two or three peptides connect at their termini, allowing both ion translocation and lipid flip-flop via a brushlike mechanism usually involving the C terminus of one peptide. The results here suggest that for some specific antimicrobial and other membrane active peptides, pore formation may not have to be invoked at all to explain peptide translocation and membrane permeabilization, which may explain why no channel structures for them have been determined experimentally.
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