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

Abstract

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.

Evaluating Polarizable Biomembrane Simulations against Experiments

“…Dynamic effects arising from electronic polarizability are thus not explicitly included, but only considered in an averaged fashion within the force field parametrization process, where parameters are obtained by fitting to macroscopic observables or to ab initio calculations. However, electronic polarization is perceived to be a key contribution to correctly describe many biomolecular systemsincluding water, ion hydration and ion binding to molecules, cation−π and π–π interactions, the vibrational Stark effect, , as well as co-operativity in interactions in general . These low-level interactions also translate to the behavior of large-scale biomolecular systems, such as ion channels where ion-selectivity and ion currents may be affected by polarization, − and telomeric DNA where the conformations adopted are mediated by ionic interactions.…”

“…However, electronic polarization is perceived to be a key contribution to correctly describe many biomolecular systems—including water, ion hydration and ion binding to molecules, cation−π and π–π interactions, 2 the vibrational Stark effect, 3 , 4 as well as co-operativity in interactions in general. 5 These low-level interactions also translate to the behavior of large-scale biomolecular systems, such as ion channels where ion-selectivity and ion currents may be affected by polarization, 6 − 9 and telomeric DNA 10 where the conformations adopted are mediated by ionic interactions. Consequently, significant efforts have been dedicated to introduce explicit polarizability into MD simulations in the hopes of reaching a more accurate representation of reality.…”

Evaluating polarizable biomembrane simulations against experiments

“…However, electronic polarization is perceived to be a key contribution to correctly describe many biomolecular systems-including water, ion hydration and ion binding to molecules, cation-π and π-π interactions, 2 the vibrational Stark 2 effect, 3,4 as well as co-operativity in interactions in general. 5 These low-level interactions also translate to the behaviour of large-scale biomolecular systems, such as ion channels where ion-selectivity and ion currents may be affected by polarization, [6][7][8][9] and telomeric DNA 10 where the conformations adopted are mediated by ionic interactions. Consequently, significant efforts have been dedicated to introduce explicit polarizability into MD simulations in the hopes of reaching a more accurate representation of reality.…”