Rational design and binding of modified cell-wall peptides to vancomycin-group antibiotics : Factorising free energy contributions to binding

Modified cell-wall peptides have been rationally designed and studied in a semi-quantitative approach to factorising free energy contributions in binding to vancomycin-group antibiotics in aqueous solution. Binding energies for succinyl and fumaryl-D-Ala dipeptides. and N-oxalyl-γ-aminobutyric acid analogues, are compared with binding energies for the natural substrate N-Ac-D-Ala-D-Ala, and the truncated mono-peptide N-Ac-D-Ala. We estimate the binding energy of the N-terminal carboxyl group, by four independent analyses, to he -(14 to 17)±7 kJ mol-1 when differences in ligand binding energies are corrected for differences in contributions from the “cost” of restricting rotations and “benefits” of hydrophobic interactions. The carboxylate interaction comprises both a charged —COO-•••HN hydrogen bond plus face to face π-stacking between the carboxylate group and an aromatic ring in the antibiotic binding pocket