Conformational and enantioselectivity in host-guest chemistry: the selective binding of cis amides examined by free energy calculations

Relative binding free energies of amino acid derivatives to the host macrobicycle 12 in chloroform are calculated to determine the effect of stereochemistry and amide bond conformation. Simulations are performed for three different amino acid derivatives using Monte Carlo simulations, free energy perturbations, and the generalized Born/surface area solvation model. The free energy results support previous experimental findings that the L enantiomers of N-acetyl phenylalanine carboxylate and N-acetyl alanine carboxylate bind preferentially over the D enantiomers and that the amide bond is in the cis conformation for the bound L enantiomers. The enantioselectivity arises because of better shape complementarity, and the cis stabilization is achieved by a selective hydrogen bond to the cavity rim of the host and a remote steric stabilization of the side-chain chi(1) dihedral angle. This computational approach was also applied to N-acetyl glycine carboxylate and indicated that, for this amino acid derivative, both the trans and the cis forms of the acetyl amide can be accommodated within the macrobicycle cavity. Experimental evidence to support this finding was obtained by detailed NMR experiments on a 1:1 complex of M12 and N-acetyl glycine. The study demonstrates two important points regarding binding and conformation: First, the destabilization of the chi(1) dihedral angle of N-acetyl phenylalanine away from the most stable conformation appears to stabilize the cis conformation of the preceding amide bond, suggesting that amino acids other than proline might be able to increase the likelihood of cis amide bonds. More generally, internal conformational coupling is an important factor to consider in molecular recognition. Second, the comprehensive sampling protocol undertaken for this relatively small system that allows the host to adjust properly to each guest is shown to be crucial in obtaining converged free energies and different binding modes. Subtle changes in host geometry have profound effects on binding. Conversely, different binding modes arising from small changes in guest conformation, chirality, or side chain serve as a reminder that binding modes are not always transferable between apparently similar molecules