Extracting Quantitative Information at Quantum Mechanical Level from Noncovalent Interaction Index Analyses.

The noncovalent interaction (NCI) index is nowadays a well-known strategy to detect NCIs in molecular systems. Even though it initially provided only qualitative descriptions, the technique has been recently extended to also extract quantitative information. To accomplish this task, integrals of powers of the electron distribution were considered, with the requirement that the overall electron density can be clearly decomposed as sum of distinct fragment contributions to enable the definition of the (noncovalent) integration region. So far, this was done by only exploiting approximate promolecular electron densities, which are given by the sum of spherically averaged atomic electron distributions and thus represent too crude approximations. Therefore, to obtain more quantum mechanically (QM) rigorous results from NCI index analyses, in this work, we propose to use electron densities obtained through the transfer of extremely localized molecular orbitals (ELMOs) or through the recently developed QM/ELMO embedding technique. Although still approximate, the electron distributions resulting from the abovementioned methods are fully QM and, above all, are again partitionable into subunit contributions, which makes them completely suitable for the NCI integral approach. Therefore, we benchmarked the integrals resulting from NCI index analyses (both those based on the promolecular densities and those based on ELMO electron distributions) against interaction energies computed at a high quantum chemical level (in particular, at the coupled cluster level). The performed test calculations have indicated that the NCI integrals based on ELMO electron densities outperform the promolecular ones. Furthermore, it was observed that the novel quantitative NCI-(QM/)ELMO approach can be also profitably exploited both to characterize and evaluate the strength of specific interactions between ligand subunits and protein residues in protein-ligand complexes and to follow the evolution of NCIs along trajectories of molecular dynamics simulations. Although further methodological improvements are still possible, the new quantitative ELMO-based technique could be already exploited in situations in which fast and reliable assessments of NCIs are crucial, such as in computational high-throughput screenings for drug discovery.