Molecular-dynamics investigation of molecular flexibility in ligand binding.

The molecular flexibility of an inhibitor in ligand-binding process has been investigated by the mass-weighted molecular-dynamics simulation, a computational method adopted from the standard molecular-dynamics simulation and one by which the conformational space of a biomolecular system over potential energy barriers can be sampled effectively. The bimolecular complex of the aspartyl proteinase from Rhizopus chinensis, rhizopuspepsin, and an octapeptide inhibitor was previously studied in a mass-weighted molecular-dynamics simulation; the study has been extended for investigating the molecular flexibility in ligand binding. A series of mass-weighted molecular-dynamics simulations was carried out in which libration of the inhibitor dihedral angles was parametrically controlled, and threshold values of dihedral angle libration amplitudes were observed from monitoring the sampling of the enzyme binding pocket by the inhibitor in the simulations. The computational results are consistent with the general notion of molecular-flexibility requirement for ligand binding; the freedom of dihedral rotations of side-chain groups was found to be particularly important for ligand binding. Thus the critical degree of molecular flexibility which would contribute to effective enzyme inhibition can be obtained precisely from the modified molecular-dynamics simulations; the procedure described herein represents a first step toward providing quantitative measures of such a molecular-flexibility index for inhibitor molecules that have been otherwise targeted for optimal protein-ligand interactions.