A free-energy simulation study of a bacterial collagenase inhibitor

The cis-trans conformational isomerisation of the N-methylated peptide bond of a bacterial collagenases peptide inhibitor (HS-CH2-CH2-CO-Pro-NMe-Ala) has been investigated by molecular dynamics simulations, energy minimisations and free-energy simulations in presence of solvent molecules. The free-energy difference between the cis and trans forms obtained by the thermodynamics integration method is equal to 0.95 kcal/mol in favour of the trans form, in accord with the experimental result. The main contribution to this free-energy difference comes from solute-water electrostatic interactions. Interestingly, we show that the number of interactions between water molecules and the oxygen atoms of the inhibitor is larger in the trans form than in the cis. Thus the organisation of water molecules around the inhibitor appears crucial in determining the population of the cis and trans conformers.