Conformational changes of small molecules binding to proteins.

Flexible molecules change their conformation upon binding to a protein. This was shown by the analysis of small molecules whose structures have been determined by X-ray crystallography of both the pure compound and the compound bound to a protein. Thirty-three compounds present both in the Cambridge Structural Database and the Brookhaven Protein Data Bank were analyzed, and both were compared with the global energy minimum conformation calculated by the molecular mechanics program CHARMm. It was found that the conformation bound to the protein differs from that in the crystal structure and also from that of the global energy minimum, and the degree of deformation depends upon the number of freely rotatable bonds in the molecule. Analysis of the conformational energies of the flexible molecules showed that, for most of those compounds, both the crystal and the protein-bound conformations are energetically well above the global minimum, and, in many cases, not even in any local energy minimum. Semi-empirical calculations performed for a select number of structures, using both the AM1 and PM3 hamiltonians, confirmed these results. These findings are discussed as to their impact upon contemporary methods of drug design.