CALCULATION OF RELATIVE BINDING OF FREE-ENERGY OF VANCOMYCIN WITH DIACETYL-L-LYSYL-D-ALANYL-D-ALANINE AND DIACETYL-L-LYSYL-L-ALANYL-L-ALANINE

By means of a free energy perturbation method implemented with molecul ar 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 wi th the D-form peptide and the complex with the L-form peptide was empl oyed as the perturbation final stage in order to overcome the difficul ties of calculating the perturbation between isomers. The calculated r elative binding of free energy was 5.15 kcal/mol in water, which compa red well with an experimental value of 8.4 kcal/mol. Structure analysi s were performed on the number of possible hydrogen bondings, the hydr ophobic interactions between peptide ligands and vancomycin, and the b onding angle between designated nuclei. The calculated structure resul ts were all well supported by the NMR data. An investigation of the re lative free energy calculation suggests that relative binding affinity in a host-guest system can be achieved by molecular dynamic simulatio n and the finite difference thermodynamic integration method.