RATIONAL DESIGN AND BINDING OF MODIFIED CELL-WALL PEPTIDES TO VANCOMYCIN-GROUP ANTIBIOTICS - FACTORIZING 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-gamma-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 be -(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 pi-stacking between the carboxylate group and an aromatic ring in the antibiotic binding pocket.