High resolution fast quantitative docking using fourier domain correlation techniques

Abstract

A 'docking' method based on finite grid forcefield sampling is proposed for fast evaluation of interaction energies between macromolecules and ligands. Forcefield used to calculate interaction energies utilizes a potential energy function composed of a 1/r-dependent electrostatic term and a (6-12) Lennard-Jones term for van der Waals interactions. Fast evaluation makes use of the convolu-tion theorem allowing a point-by-point N-dimensional correlation in direct space to be replaced by a simple multiplication in spatial frequency space. Predictive accuracy was assessed by using seven protein-ligand complexes available from the Brookhaven Data Bank and determined crystallographically to high resolution. Successful prediction of ligand position and determination of ligand-protein interaction en-thalpy was dependent on forcefield sampling grid size. Minimum interaction enthalpy calculated for four protein-ligand complexes coincided with crystallographic structures that used sampling grid sizes of 0.25 Å resolution and was independent of ligand starting position and orientation. Successful docking was obtained for the remaining complexes at same grid resolution provided ligand starting positions were not randomized. Sensitivity of the docking algorithm to starting orientation was a consequence of tight fit of respective ligand structures with their protein target sites for these three cases and can be circumvented by using finer rotational sampling grids for the ligand. Boltzmann statistics derived from calculated interaction energies successfully extracted the observed ribonuclease A cytidylic acid complex from a manifold of similar interaction energies. The proposed method was able to reproduce the observed crystallographic complex by using a dynamical description of ligand.

Treatment of reoccurring instent restenosis following reintervention after stent‐supported renal artery angioplasty

“…We can note that there is a correlation only for the low value of HINT (<0.8) or for the high value of vdW (>−0.2). The differences between vdW and HINT potentials (as mentioned above, HINT has also a vdW component) can be explained in terms of the different distance dependence of these potentials with respect to electrostatic interactions 26. The vdW potential has a distance dependence notably different and becomes predominant in intermolecular complexes27 when electrostatic interactions are not determinant.…”

Inherent limitations in protein–protein docking procedures

“…Our tests indicate that reducing the grid interval from 1.05 to 0.8 Å extends the range of distinction between NCMs and decoys by 100 Å 2 but it does not improve the statistical significance of the NCMs. Docking of small ligands to proteins using different grid intervals (0.25-2 Å ) showed that only very high-resolution grid representations (<0.4 Å ) produced good predictions (Blom and Sygusch, 1997). Working with such high resolutions is currently unrealistic in protein-protein docking because of the memory load and computation time.…”

A comprehensive review of computational techniques for the prediction of drug side effects

“…The docking of a particular molecule or certain molecules in a particular conformation or more than one conformation is performed to identify the ligands. The evaluation of the various docking procedures has shown that they are able to find the docking results that are similar to the experimental structures (Blom & Sygusch, 1997;Ewing & Kuntz, 1997;Jones, Willett, Glen, Leach, & Taylor, 1997;Morris, Goodsell, Huey, & Olson, 1996). To identify the proteins that are related to certain side effects, the data from the medical biochemistry literature (Baynes & Dominiczak, 2009) were utilized.…”