By means of a free energy perturbation method implemented with molecular dynamics, the relative binding of free energies of vancomycin with Ac-2-L-Lys-D-Ala-D-Ala and with Ac-2-L-Lys-L-Ala-L-Ala peptide ligands were calculated. A transition state between the vancomycin complex with the D-form peptide and the complex with the L-form peptide was employed as the perturbation final stage in order to overcome the difficulties of calculating the perturbation between isomers. The calculated relative binding of free energy was 5.15 kcal/mol in water, which compared well with an experimental value of 8.4 kcal/mol. Structure analysis were performed on the number of possible hydrogen bondings, the hydrophobic interactions between peptide ligands and vancomycin, and the bonding angle between designated nuclei. The calculated structure results were all well supported by the NMR data. An investigation of the relative free energy calculation suggests that relative binding affinity in a host-guest system can be achieved by molecular dynamic simulation and the finite difference thermodynamic integration method.
