Harmonic modes as variables to approximately account for receptor flexibility in ligand-receptor docking simulations: Application to DNA minor grooveligand complex

An approach to approximately account for receptor flexibility in ligand-rec eptor docking simulations is described and applied to a DNA/Hoechst 33258 a nalogue complex. Harmonic modes corresponding to eigenvectors with small ei genvalues of the Hessian matrix of the potential energy function were used as independent variables to describe receptor flexibility. For the DNA mino r groove ligand case most of the conformational difference between an energ y minimized free DNA and Ligand-bound structure could be assigned to 5-40 h armonic receptor modes with small eigenvalues. During docking, deformations of the DNA receptor structure in the subset of harmonic modes were limited using a simple penalty function that avoided the summation over all intrar eceptor atom pairs. Significant improvement of the sterical fit between lig and and receptor was found upon relaxation of the DNA in the subset of harm onic modes after docking of the ligand at the position found in the known c rystal structure. In addition, the harmonic mode relaxation resulted in DNA structures that were more similar to the energy minimized ligand-bound for m. Although harmonic mode relaxation also leads to improved sterical fit fo r other ligand placements, the placement as observed in the crystal structu re could still be identified as the site with the most favorable sterical i nteractions. Because relaxation in the harmonic modes is orders of magnitud e faster than conventional energy minimization using all atom coordinates a s independent variables, the approach might be useful as a preselection too l to recognize Ligand binding sites accessible only upon small conformation al changes of the receptor. The harmonic mode relaxed structures can only b e considered as approximate structures because deformation of the receptor in the harmonic modes can lead to small perturbations of the stereochemical geometry of the molecule. Energy minimization of preselected ligand-DNA do cking candidates in all atom coordinates is required to reduce these deviat ions. (C) 1999 John Wiley & Sons, Inc.