Computational Approaches in Peptide and Protein Design: An Overview - Peptide and Protein Design for Biopharmaceutical Applications - page 16

Despite this comparison, which distinguishes the QM/MM force field
as preferable for energy estimations in peptides and proteins, practical
applications of this approach to systems larger than the alanine dipeptide
are rather rare due to its computational demands, though several studies
have employed it [28]. On the other hand, the QM/MM approach has
already been incorporated into some molecular modelling packages, such
as a recent version of AMBER [30].
Another significant improvement to force fields emerged from a long-
standing problem to do with the correct accounting for electrostatic
interactions. In the Born-Oppenheimer approximation, the short-ranged
repulsive and attractive nonbonded forces acting between atoms can be
assigned to atomic centres to provide an estimation of the nonbonded
energy. But in reality electrostatic potentials are delocalized over the
entire molecular volume, and representing electrostatic energy simply
by sum over interactions between point changes localized on the same
atomic centres - as happens with all the force fields discussed above - is
the source of errors in electrostatic energy. Also, electrostatic potentials
for a given molecule may vary from one conformation to another, since
different spatial arrangements of the charges on the atomic centres induce
variations of those changes through dipole-dipole (and, more generally,
multipole-multipole) mechanisms. Additionally, electrostatic potentials
around polar molecules also depend on the influence of a solvent, espe-
cially a polar solvent, such as water.
In other words, delocalized electrostatic potentials depend on the
conformation of the molecule in its particular electrostatic environ-
ment, which in turn depends on electrostatic potentials. Accordingly,
the main problem in dealing with this obstacle is to develop procedures
that efficiently converge to a stable distribution of delocalized compo-
nents of electrostatic potentials for each conformation. Several types of
such procedures were suggested, leading to the new generation of the
so-called 'polarizable' force fields. Delocalization of electrostatic
potentials was achieved by employing various schemes, including the
creation of additional artificial atomic centres (e.g. 'lone pairs') and the
decomposition of the charges into sophisticated systems of multipoles.
The effect of additional polarization from water was also included in
some procedures, as were various models for water-water interactions
(see [22]). The polarizable force fields aiming at possible applications
for peptides and proteins were suggested by several groups (e.g.
[22,31]) and showed improvements in energy estimations of local
minima on the Ramachandran map of Ac-Ala-OMe. The typical
benchmark for validation of polarizable force fields was the ability to