Harmonic modes as variables to approximately account for receptor flexibility in ligand-receptor docking simulations: Application to DNA minor groove ligand complex
✍ Scribed by Zacharias, Martin; Sklenar, Heinz
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 325 KB
- Volume
- 20
- Category
- Article
- ISSN
- 0192-8651
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✦ Synopsis
An approach to approximately account for receptor flexibility in ligand᎐receptor docking simulations is described and applied to a DNArHoechst 33258 analogue complex. Harmonic modes corresponding to eigenvectors with small eigenvalues of the Hessian matrix of the potential energy function were used as independent variables to describe receptor flexibility. For the DNA minor groove ligand case most of the conformational difference between an energy minimized free DNA and ligand-bound structure could be assigned to 5᎐40 harmonic 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 intrareceptor atom pairs. Significant improvement of the sterical fit between ligand and receptor was found upon relaxation of the DNA in the subset of harmonic modes after docking of the ligand at the position found in the known crystal structure. In addition, the harmonic mode relaxation resulted in DNA structures that were more similar to the energy minimized ligand-bound form. Although harmonic mode relaxation also leads to improved sterical fit for other ligand placements, the placement as observed in the crystal structure could still be identified as the site with the most favorable sterical interactions. Because relaxation in the harmonic modes is orders of magnitude faster than conventional energy minimization using all atom coordinates as independent variables, the approach might be useful as a preselection tool to