On the Applicability
of Elastic Network Normal Modes in Small-Molecule Docking
- Publication date
- Publisher
Abstract
Incorporating backbone flexibility into protein–ligand
docking
is still a challenging problem. In protein–protein docking,
normal mode analysis (NMA) has become increasingly popular as it can
be used to describe the collective motions of a biological system,
but the question of whether NMA can also be useful in predicting the
conformational changes observed upon small-molecule binding has only
been addressed in a few case studies. Here, we describe a large-scale
study on the applicability of NMA for protein–ligand docking
using 433 apo/holo pairs of the Astex data sets. On the basis of sets
of the first normal modes from the apo structure, we first generated
for each paired holo structure a set of conformations that optimally
reproduce its C<sub>α</sub> trace with respect to the underlying
normal mode subspace. Using AutoDock, GOLD, and FlexX we then docked
the original ligands into these conformations to assess how the docking
performance depends on the number of modes used to reproduce the holo
structure. The results of our study indicate that, even for such a
best-case scenario, the use of normal mode analysis in small-molecule
docking is restricted and that a general rule on how many modes to
use does not seem to exist or at least is not easy to find