Lipid Composition Is Critical for Accurate Membrane Permeability Prediction of Cyclic Peptides by Molecular Dynamics Simulations

Cyclic peptides have attracted attention as a promising
pharmaceutical
modality due to their potential to selectively inhibit previously
undruggable targets, such as intracellular protein–protein
interactions. Poor membrane permeability is the biggest bottleneck
hindering successful drug discovery based on cyclic peptides. Therefore,
the development of computational methods that can predict membrane
permeability and support elucidation of the membrane permeation mechanism
of drug candidate peptides is much sought after. In this study, we
developed a protocol to simulate the behavior in membrane permeation
steps and estimate the membrane permeability of large cyclic peptides
with more than or equal to 10 residues. This protocol requires the
use of a more realistic membrane model than a single-lipid phospholipid
bilayer. To select a membrane model, we first analyzed the effect
of cholesterol concentration in the model membrane on the potential
of mean force and hydrogen bonding networks along the direction perpendicular
to the membrane surface as predicted by molecular dynamics simulations
using cyclosporine A. These results suggest that a membrane model
with 40 or 50 mol % cholesterol was suitable for predicting the permeation
process. Subsequently, two types of membrane models containing 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and 40 and 50 mol % cholesterol
were used. To validate the efficiency of our protocol, the membrane
permeability of 18 ten-residue peptides was predicted. Correlation
coefficients of R > 0.8 between the experimental
and calculated permeability values were obtained with both model membranes.
The results of this study demonstrate that the lipid membrane is not
just a medium but also among the main factors determining the membrane
permeability of molecules. The computational protocol proposed in
this study and the findings obtained on the effect of membrane model
composition will contribute to building a schematic view of the membrane
permeation process. Furthermore, the results of this study will eventually
aid the elucidation of design rules for peptide drugs with high membrane
permeability.