Unlike other methods for docking ligands to the rigid 3D structure of a known protein receptor, Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand. In this search, an initial rough positioning and scoring phase that dramatically narrows the search space is followed by torsionally flexible energy optimization on an OPLS-AA nonbonded potential grid for a few hundred surviving candidate poses. The very best candidates are further refined via a Monte Carlo sampling of pose conformation; in some cases, this is crucial to obtaining an accurate docked pose. Selection of the best docked pose uses a model energy function that combines empirical and force-field-based terms. Docking accuracy is assessed by redocking ligands from 282 cocrystallized PDB complexes starting from conformationally optimized ligand geometries that bear no memory of the correctly docked pose. Errors in geometry for the top-ranked pose are less than 1 A in nearly half of the cases and are greater than 2 A in only about one-third of them. Comparisons to published data on rms deviations show that Glide is nearly twice as accurate as GOLD and more than twice as accurate as FlexX for ligands having up to 20 rotatable bonds. Glide is also found to be more accurate than the recently described Surflex method.
Atomic Born radii (α) are used in the generalized Born (GB)
equation to calculate approximations to the
electrical polarization component (G
pol) of
solvation free energy. We present here a simple analytical
formula
for calculating Born radii rapidly and with useful accuracy. The
new function is based on an atomic pairwise
r
ij
-4
treatment and contains several empirically determined parameters that
were established by optimization
against a data set of >10 000 accurate Born radii computed
numerically using the Poisson equation on a
diverse group of organic molecules, molecular complexes, oligopeptides,
and a small protein. Coupling this
new Born radius calculation with the previously described GB/SA
solvation treatment provides a fully analytical
solvation model that is computationally efficient in comparison with
traditional molecular solvent models
and also affords first and second derivatives. Tests with the
GB/SA model and Born radii calculated with
our new analytical function and with the accurate but more
time-consuming Poisson−Boltzmann methods
indicate that comparable free energies of solventlike dielectric
polarization can be obtained using either method
and that the resulting GB/SA solvation free energies compare well with
the experimental results on small
molecules in water.
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