The variety of possible adducts with explicit water molecules is extremely high
for a solute molecule like ARZ, which contains a high number of H-bond donor or
acceptor sites and can form a variety of conformers in which one or another site
may be more or less available to form H-bonds with water molecules. It was opted
to consider all the lower energy conformers of the #1 and #3 series and representative higher energy ones, to ensure that the most interesting arrangements of
water molecules around the various sites of ARZ are captured.
Two sets of adducts were considered. One set involves most of the conformers
of the #1 and #3 series, and entails adducts in which one water molecules is
attached in turn to each donor or acceptor site of each conformer. These adducts
enable a comparison of the energy with which each site can bind a water molecule,
and also offer indications about how close a water molecule can approach the given
site. In the real situation within the solvent, this is determined also by the interactions between water molecules and, therefore, a water molecule attached to a
given site might remain at a greater distance than in the models with only one water
molecule. On the other hand, it may happen that one (or, sometimes, more) water
molecules remain attached to the solute molecule when it enters the active site of
the biological target and may contribute to the binding between the molecule and
the target; in such cases, the water molecule will likely remain as close as possible
to the ARZ site to which it binds. The knowledge of the strength with which a water
molecule binds to a certain donor or acceptor site of ARZ may thus be useful also
for a better understanding of its permanence (when it occurs) when ARZ binds to its
target, or its role in such binding.
The second set comprises adducts with several explicit water molecules,
attempting to approximate a first solvation layer or portions of it. Like in previous
studies on adducts of ACPLs with explicit water molecules [16, 17, 19], the ‘first
solvation layer’ concept is expanded to include not only the water molecules
directly H-bonded to suitable sites of the solute molecule, but also water molecules
that might bridge them (the presence of a third water molecule bridging two
molecules directly H-bonded to the solute often has a stabilizing effect [17]). The
distribution and spacing of the several H-bond donors or acceptors in ARZ enable
the possibility of considering adducts in which the water molecules attached to
ARZ, and those bridging them, approximate a continuous layer in the vicinity of
extensive portions of ARZ.
The inputs were prepared placing water molecules in the vicinity of H-bond
donor or acceptor sites of the selected conformers of ARZ. Different numbers and
arrangements of water molecules were considered for each conformer, also taking
into account the resulting arrangements of already optimised outputs. For instance,
when one or more water molecules ‘moved’ into a second solvation layer on
optimization (out of contact with the ARZ molecule and with no bridging role
between water molecules attached to it), those molecules were removed and the
resulting input was optimised as a new adduct.
The selection of the number/s of water molecule in the adducts likely to better
contribute the desired information is a rather delicate issue. Too small a number
would not enable the incorporation of the effects of water-water interactions
Adducts of Arzanol with Explicit Water Molecules …
285
for a solute molecule like ARZ, which contains a high number of H-bond donor or
acceptor sites and can form a variety of conformers in which one or another site
may be more or less available to form H-bonds with water molecules. It was opted
to consider all the lower energy conformers of the #1 and #3 series and representative higher energy ones, to ensure that the most interesting arrangements of
water molecules around the various sites of ARZ are captured.
Two sets of adducts were considered. One set involves most of the conformers
of the #1 and #3 series, and entails adducts in which one water molecules is
attached in turn to each donor or acceptor site of each conformer. These adducts
enable a comparison of the energy with which each site can bind a water molecule,
and also offer indications about how close a water molecule can approach the given
site. In the real situation within the solvent, this is determined also by the interactions between water molecules and, therefore, a water molecule attached to a
given site might remain at a greater distance than in the models with only one water
molecule. On the other hand, it may happen that one (or, sometimes, more) water
molecules remain attached to the solute molecule when it enters the active site of
the biological target and may contribute to the binding between the molecule and
the target; in such cases, the water molecule will likely remain as close as possible
to the ARZ site to which it binds. The knowledge of the strength with which a water
molecule binds to a certain donor or acceptor site of ARZ may thus be useful also
for a better understanding of its permanence (when it occurs) when ARZ binds to its
target, or its role in such binding.
The second set comprises adducts with several explicit water molecules,
attempting to approximate a first solvation layer or portions of it. Like in previous
studies on adducts of ACPLs with explicit water molecules [16, 17, 19], the ‘first
solvation layer’ concept is expanded to include not only the water molecules
directly H-bonded to suitable sites of the solute molecule, but also water molecules
that might bridge them (the presence of a third water molecule bridging two
molecules directly H-bonded to the solute often has a stabilizing effect [17]). The
distribution and spacing of the several H-bond donors or acceptors in ARZ enable
the possibility of considering adducts in which the water molecules attached to
ARZ, and those bridging them, approximate a continuous layer in the vicinity of
extensive portions of ARZ.
The inputs were prepared placing water molecules in the vicinity of H-bond
donor or acceptor sites of the selected conformers of ARZ. Different numbers and
arrangements of water molecules were considered for each conformer, also taking
into account the resulting arrangements of already optimised outputs. For instance,
when one or more water molecules ‘moved’ into a second solvation layer on
optimization (out of contact with the ARZ molecule and with no bridging role
between water molecules attached to it), those molecules were removed and the
resulting input was optimised as a new adduct.
The selection of the number/s of water molecule in the adducts likely to better
contribute the desired information is a rather delicate issue. Too small a number
would not enable the incorporation of the effects of water-water interactions
Adducts of Arzanol with Explicit Water Molecules …
285