4 Discussion and Conclusions
A study of the type considered in this work involves a variety of challenges because
of the nature of the adducts and of the character of the information that can be
obtained.
The high number of conformers of the ARZ molecule and the high number of its
H-bond donor or acceptor site implies an enormous number of possible adducts
with a given number of water molecules, and this number increases rapidly as the
number of water molecules in the adducts increases. Calculations show high sensitivity of the optimisation procedure to small differences in the inputs, which
would recommend the consideration of several adducts with similar or very similar
(but not identical) input geometries for each relevant geometry, thus further multiplying the number of potentially interesting adducts. On the other hand, the tendency of water molecules to cluster on optimisation may yield similar adducts from
different inputs, which decreases the informative role of the result. It may also lead
to adducts where some water molecules cluster beyond the boundaries of the
adopted criterion for the definition of ‘first solvation layer’, resulting in high
water-water interaction energy and poor solute-water interaction energy; since the
latter phenomenon is more extensive as the number of water molecules in the
adduct increases, it prevents the possibility of considering a higher number of water
molecules than the one for which their clustering becomes extensive or dominant.
The huge number of adducts that would be needed to provide a comprehensive
panoramic taking into account all the relevant energy-influencing features (all the
geometrical features of all the conformers of ARZ, and all the possible arrangements of water molecules around each conformer) would imply enormous computational costs. Therefore, it was opted to select representative adducts for each
relevant characteristic. This corresponds to a sampling approach more than to an
unaffordable exhaustive approach. All the same, a sampling approach can be
informative for a variety of aspects.
Within the reality of a water solution, the supermolecular structures of the
adducts are not ‘fixed’ in time, because the water molecules H-bonded to a solute
molecule do not remain the same in time (there is continuous fast interchange with
the surrounding water molecules). Therefore, the calculated adducts represent
time-averaged probable possibilities rather than permanent structures.
Despite all these challenges, the calculation of adducts with explicit water
molecules provides information on the relative strength with which a water molecule can bind to each donor or acceptor site of the solute molecule, on the distance
to which a water molecule preferably approaches each site, and on the preferred
arrangements of water molecules around each donor or acceptor sites or around the
region of two or more spatially close donors or acceptors. Since it results from
optimisation and H-bonds are directional, this information can be considered as
responding to the more common situations in the vicinity of the donors or acceptors
of the solute molecule. The adducts also provide indications about whether a certain
IHB tends to remain or to break in water solution—a type of information which
302
L. Mammino
A study of the type considered in this work involves a variety of challenges because
of the nature of the adducts and of the character of the information that can be
obtained.
The high number of conformers of the ARZ molecule and the high number of its
H-bond donor or acceptor site implies an enormous number of possible adducts
with a given number of water molecules, and this number increases rapidly as the
number of water molecules in the adducts increases. Calculations show high sensitivity of the optimisation procedure to small differences in the inputs, which
would recommend the consideration of several adducts with similar or very similar
(but not identical) input geometries for each relevant geometry, thus further multiplying the number of potentially interesting adducts. On the other hand, the tendency of water molecules to cluster on optimisation may yield similar adducts from
different inputs, which decreases the informative role of the result. It may also lead
to adducts where some water molecules cluster beyond the boundaries of the
adopted criterion for the definition of ‘first solvation layer’, resulting in high
water-water interaction energy and poor solute-water interaction energy; since the
latter phenomenon is more extensive as the number of water molecules in the
adduct increases, it prevents the possibility of considering a higher number of water
molecules than the one for which their clustering becomes extensive or dominant.
The huge number of adducts that would be needed to provide a comprehensive
panoramic taking into account all the relevant energy-influencing features (all the
geometrical features of all the conformers of ARZ, and all the possible arrangements of water molecules around each conformer) would imply enormous computational costs. Therefore, it was opted to select representative adducts for each
relevant characteristic. This corresponds to a sampling approach more than to an
unaffordable exhaustive approach. All the same, a sampling approach can be
informative for a variety of aspects.
Within the reality of a water solution, the supermolecular structures of the
adducts are not ‘fixed’ in time, because the water molecules H-bonded to a solute
molecule do not remain the same in time (there is continuous fast interchange with
the surrounding water molecules). Therefore, the calculated adducts represent
time-averaged probable possibilities rather than permanent structures.
Despite all these challenges, the calculation of adducts with explicit water
molecules provides information on the relative strength with which a water molecule can bind to each donor or acceptor site of the solute molecule, on the distance
to which a water molecule preferably approaches each site, and on the preferred
arrangements of water molecules around each donor or acceptor sites or around the
region of two or more spatially close donors or acceptors. Since it results from
optimisation and H-bonds are directional, this information can be considered as
responding to the more common situations in the vicinity of the donors or acceptors
of the solute molecule. The adducts also provide indications about whether a certain
IHB tends to remain or to break in water solution—a type of information which
302
L. Mammino