Rescaling of Point Charges as a Way to Improve the Simple-to-Use Electrostatic Embedding Scheme Developed to Explore Enzyme Activity with QM-Oriented Software

Computer-aided exploration of enzymatic reactions, which
still
leaves many important questions open, calls for robust and accurate
techniques of molecular modeling. One of the most intriguing issues
related to enzymatic reactions is the role of electrostatic interactions
established between the reacting moiety and its enzymatic environment.
In order to evaluate these interactions, we previously devised a QM/MM
scheme based on electrostatic embedding of the reaction kernel, treated
by quantum chemistry, into the enzymatic surroundings represented
by point charges [A. Prah et al., ACS Catal. 2019, 9, 1231.]. The method features remarkable simplicity
and reliably predicts the effect of electrostatics on enzyme catalysis.
Yet, this simplified approach has pitfalls; in particular, it tends
to overestimate the attracting force between the electrons and the
surrounding point chargesan effect named electron spill-outimpairing
the accuracy of evaluated electrostatic interactions. Herein, by using
statistical methods together with reference quantum calculations,
we critically assess the impact of this pitfall and propose a very
simple but effective correction based on attenuation of point charges
near the QM–MM boundary depending on their distance from the
quantum subsystem. We demonstrate that the proposed correction can
significantly improve the accuracy of computed energies of electrostatic
interactions between the reaction kernel and its enzyme surroundings,
thereby representing an important methodological advance of our electrostatic
embedding approach. Noteworthily, the optimal attenuation scheme can
vary among the considered systemsin particular, it is sensitive
to the net charge of the reaction kernelsuggesting the scheme
be tuned individually for each considered enzymatic reaction following
the presented workflow.