Benefits of the Electronic Continuum Correction in Bio-Force Fields

Abstract

The interplay between charged groups in biosystems is ubiquitous. They are crucial when considering ions, but also for many other biomolecules. Interestingly, the amount of evidence suggesting an overestimation of the interaction between charged groups in classical molecular dynamics (MD) simulations for biosystems keeps increasing. Notorious examples are lipid membranes, proteins rich in charged amino acids, and even charged sugar biopolymers when interacting with other charged species. Furthermore, the overestimation is especially dramatic when interacting with divalent ions like Ca2+. MD force fields have started to introduce empirical corrections (NBFIX). These corrections artificially increase the interatomic distance between charged atoms, effectively reducing overbinding. There is, however, a reason behind the overbinding. MD simulations can correctly capture the nuclear part of the molecular polarization, which wants to orient any molecule to the local electric field. However, they miss the electronic polarizability, which ultimately shields interacting charges. The electronic continuum correction (ECC) can recover this missing contribution. This mean-field approach provides a cheap while physically sound fix that mostly consists of scaling down the partial charges within a charged group. In this work, we present the ECC correction for the widely used CHARMM36 force field. We provide five lipid families (PI, PC, PE, PS, and PG), charged amino acids, and few sugar moieties (Glucuronic, iduronic and sialic acids). We show that the ECC correction dramatically improves their interaction with other charged groups when comparing to osmotic coefficients or NMR data. We also show that the resulting molecular structure is not worsened as compared to the original force field. Occasionally, the structure is even improved when benchmarked against experimental Raman/NMR spectra of the moieties in solution. Overall, our results show how CHARMM36 can benefit from the adoption of the ECC approach for future improvements.