Simulating the Permeation of a Therapeutic Peptide through a Phospholipid Membrane

Abstract

Oral peptide delivery offers a promising route for therapeutic administration but is often hampered by challenges related to the low permeability of peptides across gastrointestinal epithelia. This study employs state-of-the-art molecular dynamics (MD) simulations and enhanced sampling methods (i.e., well-tempered metadynamics extended-system adaptive biasing force, coined WTM-eABF) to investigate the simultaneous folding/unfolding of a linear 39 amino acid peptide with and without a fatty acid modification as it permeates a POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) membrane. The resulting free energy surfaces capture the simultaneous secondary structural changes and the translocation process of the peptides, which are carefully examined against well-established, independent free-energy calculations at key steps in the permeation process. The free-energy surfaces indicate that the peptides assume a more structured configuration upon membrane interaction. The results show that the permeation of neutral peptides, despite their large size, is nearly barrierless. In addition, the simulations show that WTM-eABF is able to qualitatively converge the free energy of the permeation of long, flexible peptides.