Home >

news Help

Publication Information


Title
Japanese: 
English:Lipid Composition Is Critical for Accurate Membrane Permeability Prediction of Cyclic Peptides by Molecular Dynamics Simulations 
Author
Japanese: 杉田 昌岳, 藤江拓哉, 柳澤 渓甫, 大上 雅史, 秋山 泰.  
English: Masatake Sugita, Takuya Fujie, Keisuke Yanagisawa, Masahito Ohue, Yutaka Akiyama.  
Language English 
Journal/Book name
Japanese: 
English:Journal of Chemical Information and Modeling 
Volume, Number, Page Volume 62    Issue 18    pp. 4549-4560
Published date Sept. 2, 2022 
Publisher
Japanese: 
English:American Chemical Society 
Conference name
Japanese: 
English: 
Conference site
Japanese: 
English: 
Official URL https://pubs.acs.org/doi/10.1021/acs.jcim.2c00931
 
DOI https://doi.org/10.1021/acs.jcim.2c00931
Abstract 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.

©2007 Institute of Science Tokyo All rights reserved.