CONFORMATIONAL ENERGY PENALTIES OF PROTEIN-BOUND LIGANDS

The conformational energies required for ligands to adopt their bioact ive conformations were calculated for 33 ligand-protein complexes incl uding 28 different ligands. In order to monitor the force field depend ence of the results, two force fields, MM3 and AMBER*, were employed for the calculations. Conformational analyses were performed in vacuo and in aqueous solution by using the generalized Born/solvent accessib le surface (GB/SA) solvation model. The protein-bound conformations we re relaxed by using flat-bottomed Cartesian constraints. For about 70% of the ligand-protein complexes studied, the conformational energies of the bioactive conformations were calculated to be less than or equa l to 3 kcal/mol. It is demonstrated that the aqueous conformational en semble for the unbound ligand must be used as a reference state in thi s type of calculations. The calculations for the ligand-protein comple xes with conformational energy penalties of the ligand calculated to b e larger than 3 kcal/mol suffer from uncertainties in the interpretati on of the experimental data or limitations of the computational method s. For example, in the case of long-chain flexible ligands (e.g, fatty acids), it is demonstrated that several conformations may be found wh ich are very similar to the conformation determined by X-ray crystallo graphy and which display significantly lower conformational energy pen alties for binding than obtained by using the experimental conformatio n. For strongly polar molecules, e.g. amino acids, the results indicat e that further developments of the force fields and of the dielectric continuum solvation model are required for reliable calculations on th e conformational properties of this type of compounds.