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Computational screening of branched cyclic peptide motifs as potential enzyme mimetics
Author(s) -
Stavrakoudis Athanassios,
Makropoulou Sevasti,
Tsikaris Vassilios,
SakarellosDaitsiotis Maria,
Sakarellos Constantinos,
Demetropoulos Ioannis N.
Publication year - 2003
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.441
Subject(s) - catalytic triad , molecular dynamics , chemistry , stereochemistry , molecular model , peptide , molecule , solvation , in silico , protein superfamily , serine protease , serine , residue (chemistry) , combinatorial chemistry , protease , enzyme , computational chemistry , biochemistry , organic chemistry , gene
In a previous work we described the design, synthesis and catalytic activity of a branched cyclic peptide as a serine protease mimic. To maximize its catalytic activity we present now a systematic search of a large number of homologous peptides for potential enzyme activity as revealed by the topological arrangement of the catalytic triad residues. This process is accomplished by applying a combined molecular mechanics and molecular dynamics conformational search of about 200 molecules. Starting from a previously synthesized compound that showed some hydrolytic activity several analogues were modelled by amino acid substitutions in the main molecular framework using the Insight II molecular modelling environment with some script automation. Also presented is an algorithm that: (a) generates all possible combinations of residue substitutions, (b) scans the conformational space for each molecule via high temperature molecular dynamics, (c) picks the set of molecules the trajectories of which retained, to a considerable degree, the catalytic triad molecular arrangement, (d) subjects the selected molecules to layer solvation and energy minimization and chooses the molecules, the conformations of which could preserve the catalytic triad arrangement. Finally, a modelling with periodic boundary conditions, was performed to further support the reported algorithm. We found that at least one of the analogues could be a potential serine protease mimic, as revealed by the root‐mean‐square comparison between the catalytic triad in two molecular dynamics trajectories of the peptide and the corresponding residues in the crystal structure of trypsin. The most promising model candidate was synthesized and tested for its catalytic activity. Copyright © 2003 European Peptide Society and John Wiley & Sons, Ltd.