improve their performance [9–11], there is a persisting challenge to
predict proper positions of water molecules on the surface of the
unbound receptor, which is required when its crystal structure with
a ligand is unknown. Even if the structure of unbound receptor is
available from X-ray scattering experiments with a high resolution,
some of the observed water molecules present in the unbound
receptor could be displaced upon binding of a ligand. Moreover,
X-ray data represent only a structural snapshot of the receptor
molecule which reveals a highly dynamic behavior, therefore ren-
dering the data on solvent positions ambiguous and incomplete
[12]. In this chapter, we present methodological details on two
methods we developed to include explicit solvent into molecular
docking studies: (1) we use atomic probes to de novo predict
energetically favorable positions of water molecules on the receptor
surface and, furthermore, to exclude water molecules that are
supposed to be displaced upon ligand binding [13]; (2) We use
fully flexible receptor and ligand in explicit solvent to carry out
docking experiments applying targeted molecular dynamics (MD)
techniques [14].
Both methods yielded promising results when applied to repre-
sentative datasets of protein–GAG systems. Here, we discuss their
particular features and describe their applicability and limitations
one should be aware of.2 Methods
2.1 De Novo
Placement of Explicit
Water Molecules on
the Protein Surface in
the Putative Binding
Site Prior to Docking
Application of this method allows to explicitly account for solvent
as a part of the receptor in molecular docking considering both
water molecules which occupy the same hydration sites in unbound
and bound protein receptor and the ones potentially displaced
upon ligand binding.- The starting structure of the protein receptor in one of the
standard molecular formats (pdb, mol2, mol, etc.) could be of
experimental origin and downloaded from the PDB or a mod-
eled structure. - In case it is an experimental structure obtained by X-ray scat-
tering, all experimental water molecules should be removed
from the receptor structure (seeNote 1). - Ligands and ions should be removed from the protein surface/
binding site where the predictions are to be carried out (see
Note 2). - A complete receptor molecule (for global docking) or receptor
residues in the binding site (for local docking) should be energy
minimized (seeNote 3). In our original study [13], we used the
AMBER 99 force field as implemented in MOE (combination
446 Sergey A. Samsonov