Cooperativity and Frustration Effects (or Lack Thereof) in Polarizable and Non-polarizable Force Fields

Understanding cooperativity and frustration is crucial
for studying
biological processes such as molecular recognition and protein aggregation.
Force fields have been extensively utilized to explore cooperativity
in the formation of protein secondary structures and self-assembled
systems. Multiple studies have demonstrated that polarizable force
fields provide more accurate descriptions of this phenomenon compared
to fixed-charge pairwise nonpolarizable force fields, thanks to the
incorporation of polarization effects. In this study, we assess the
performance of the AMOEBA polarizable force field and the AMBER and
OPLS nonpolarizable pairwise force fields in capturing positive and
negative cooperativity recently explored in neutral and charged molecular
clusters using density functional theory. Our findings show that polarizable
and nonpolarizable force fields qualitatively reproduce the relative
cooperativity observed in electron structure calculations. However,
AMBER and OPLS fail to describe absolute cooperativity. In contrast,
AMOEBA accounts for the absolute cooperativity by considering interactions
beyond pairwise interactions. According to the energy decomposition
analysis, it is observed that the electrostatic interactions calculated
with the AMBER and OPLS force fields seem to play an important and
counterintuitive role in reproducing the adiabatic interaction energies
calculated with density functional theory. However, it is important
to note that these force fields, due to their nature, do not explicitly
incorporate many-body effects, which limits their ability to accurately
describe cooperativity. On the other hand, frustration in polarizable
and nonpolarizable force fields is caused by changes in bond stretching
and angle bending terms of the building blocks when they are forming
a complex.