Large-Scale Membrane Permeability Prediction of Cyclic Peptides Crossing a Lipid Bilayer Based on Enhanced Sampling Molecular Dynamics Simulations

Membrane permeability
is a significant obstacle facing the development
of cyclic peptide drugs. However, membrane permeation mechanisms are
poorly understood. To investigate common features of permeable (and
nonpermeable) designs, it is necessary to reproduce the membrane permeation
process of cyclic peptides through the lipid bilayer. We simulated
the membrane permeation process of 100 six-residue cyclic peptides
across the lipid bilayer based on steered molecular dynamics (MD)
and replica-exchange umbrella sampling simulations and predicted membrane
permeability using the inhomogeneous solubility-diffusion model and
a modified version of it. Furthermore, we confirmed the effectiveness
of this protocol by predicting the membrane permeability of 56 eight-residue
cyclic peptides with diverse chemical structures, including some confidential
designs from a pharmaceutical company. As a result, a reasonable correlation
between experimentally assessed and calculated membrane permeability
of cyclic peptides was observed for the peptide libraries, except
for strongly hydrophobic peptides. Our analysis of the MD trajectory
demonstrated that most peptides were stabilized in the boundary region
between bulk water and membrane and that for most peptides, the process
of crossing the center of the membrane is the main obstacle to membrane
permeation. The height of this barrier is well correlated with the
electrostatic interaction between the peptide and the surrounding
media. The structural and energetic features of the representative
peptide at each vertical position within the membrane were also analyzed,
revealing that peptides permeate the membrane by changing their orientation
and conformation according to the surrounding environment.