期刊
JOURNAL OF CHEMICAL INFORMATION AND MODELING
卷 61, 期 7, 页码 3681-3695出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.1c00380
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类别
资金
- Program for Building Regional Innovation Ecosystems Program to Industrialize an Innovative Middle Molecule Drug Discovery Flow through Fusion of Computational Drug Design and Chemical Synthesis Technology from Ministry of Education, Culture, Sports, Scie
- KAKENHI from Japan Society for the Promotion of Science (JSPS) [17H01814, 20H04280]
- Japan Science and Technology Agency (JST)
- AIST-TokyoTech Real World Big-Data Computation Open Innovation Laboratory (RWBC-OIL) from the National Institute of Advanced Industrial Science and Technology (AIST)
- Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from the Japan Agency for Medical Research and Development (AMED) [JP20am0101112]
- Grants-in-Aid for Scientific Research [20H04280] Funding Source: KAKEN
The study investigated the membrane permeation process of cyclic peptides across the lipid bilayer and found that crossing the center of the membrane is the main obstacle to membrane permeation, with barrier height correlated to electrostatic interactions. Peptides were observed to change orientation and conformation according to the surrounding environment to permeate the membrane.
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.
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