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

Masatake Sugita,Yutaka Akiyama,Keisuke Yanagisawa,Masahito Ohue,Yasushi Yoshikawa,Takuya Fujie,Satoshi Sugiyama

doi:10.1021/acs.jcim.1c00380

Abstract

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.

Highlights

Most pharmaceutical drugs, namely small molecules and antibody drugs, are unable to interact with 75% of potential drug targets.[1]
The most common feature of the profiles is that there is a distinctive minimum around z = 10 Å. This position is slightly inside the lipid head groups, where the hydrophobic groups can interact with the lipid tails, and the hydrophilic groups can interact with water molecules and lipid heads
The hydrophobic groups are oriented toward the center of the membrane, and some hydrogen donor and acceptor atoms interact with water molecules

Summary

Introduction

Namely small molecules and antibody drugs, are unable to interact with 75% of potential drug targets.[1]. Antibody drugs have a higher molecular weight and cannot access intracellular targets. This means that many drug molecules on the market display difficulty targeting an intracellular protein−protein interaction (PPI) interface, which accounts for a major portion of potential drug targets. It has been suggested that cyclic peptides have the potential to target “undruggable” targets, such as intracellular PPI. Certain cyclic peptides exhibit membrane permeability due to a molecular weight lower than that of antibody drugs. Well-designed cyclic peptides can inhibit intracellular PPIs. The immunosuppressant cyclosporine A (CSA) is a well-known cyclic peptide that can penetrate cells and interact with intracellular targets.[2] Cyclic peptide drugs have shown promise over the years, and many pharmaceutical companies are actively developing these drugs

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Discussion

Conclusion