Affiliation:
1. Laboratory of Structural Bioinformatics Institute of Biomedical Chemistry Pogodinskaya str., 10 Moscow 119121 Russia
2. Laboratory of Peptide Engineering Institute of Biomedical chemistry Pogodinskaya str., 10 Moscow 119121 Russia
Abstract
AbstractKnottins are very stable peptides (also called miniproteins) containing approximately 30 amino acid residues. Their structures are stabilized by three disulfide bonds forming a characteristic ‘pseudo‐knotted’ structure. This research was devoted to the design of potential inhibitors of human hepatitis C (HCV) NS3 protease by means of knottin fold using loop grafting, amino acid residues replacements and L/D amino acid epimerization. The initial structure used for design was a trypsin inhibitor from Momordica cochinchinensis seeds, MCOTI‐II. Modifications of the knottin template for optimization of the NS3 protease‐peptide interaction included deletion of several residues from the N‐terminus, replacement of residues in‐ and outside the inhibitor loop and replacement of certain L‐amino acids by their D‐stereoisomers. Stability of modified knottins and their complexes with HCV protease were evaluated by molecular dynamics simulation. Binding energy values for protein‐knottin complexes were calculated by MM‐GBSA method. The designed modified knottin characterized by the highest stability of the complex with HCV NS3 protease, was proposed for further experimental testing.