Improving
Docking Results via Reranking of Ensembles
of Ligand Poses in Multiple X‑ray Protein Conformations with
MM-GBSA
P. A. Greenidge
C. Kramer
J.-C. Mozziconacci
W. Sherman
10.1021/ci5003735.s003
https://acs.figshare.com/articles/dataset/Improving_Docking_Results_via_Reranking_of_Ensembles_of_Ligand_Poses_in_Multiple_X_ray_Protein_Conformations_with_MM_GBSA/2241562
There is a tendency in the literature
to be critical of scoring
functions when docking programs perform poorly. The assumption is
that existing scoring functions need to be enhanced or new ones developed
in order to improve the performance of docking programs for tasks
such as pose prediction and virtual screening. However, failures can
result from either sampling or scoring (or a combination of the two),
although less emphasis tends to be given to the former. In this work,
we use the programs GOLD and Glide on a high-quality data set to explore
whether failures in pose prediction and binding affinity estimation
can be attributable more to sampling or scoring. We show that identification
of the correct pose (docking power) can be improved by incorporating
ligand strain into the scoring function or rescoring an ensemble of
diverse docking poses with MM-GBSA in a postprocessing step. We explore
the use of nondefault docking settings and find that enhancing ligand
sampling also improves docking power, again suggesting that sampling
is more limiting than scoring for the docking programs investigated
in this work. In cross-docking calculations (docking a ligand to a
noncognate receptor structure) we observe a significant reduction
in the accuracy of pose ranking, as expected and has been reported
by others; however, we demonstrate that these alternate poses may
in fact be more complementary between the ligand and the rigid receptor
conformation, emphasizing that treating the receptor rigidly is an
artificial constraint on the docking problem. We simulate protein
flexibility by the use of multiple crystallographic conformations
of a protein and demonstrate that docking results can be improved
with this level of protein sampling. This work indicates the need
for better sampling in docking programs, especially for the receptor.
This study also highlights the variable descriptive value of RMSD
as the sole arbiter of pose replication quality. It is shown that
ligand poses within 2 Å of the crystallographic one can show
dramatic differences in calculated relative protein–ligand
energies. MM-GBSA rescoring of distinct poses overcomes some of the
sensitivities of pose ranking experienced by the docking scoring functions
due to protein preparation and binding site definition.
2014-10-27 00:00:00
nondefault docking settings
docking power
ligand
binding site definition
binding affinity estimation
docking programs
sampling
noncognate receptor structure
protein
RMSD