The NCIWEB Server: A Novel Implementation of the Noncovalent Interactions Index for Biomolecular Systems.

It is well-known that the activity and function of proteins is strictly correlated with their secondary, tertiary, and quaternary structures. Their biological role is regulated by their conformational flexibility and global fold, which, in turn, is largely governed by complex noncovalent interaction networks. Because of the large size of proteins, the analysis of their noncovalent interaction networks is challenging, but can provide insights into the energetics of conformational changes or protein-protein and protein-ligand interactions. The noncovalent interaction (NCI) index, based on the reduced density gradient, is a well-established tool for the detection of weak contacts in biological systems. In this work, we present a web-based application to expand the use of this index to proteins, which only requires a molecular structure as input and provides a mapping of the number, type, and strength of noncovalent interactions. Structure preparation is automated and allows direct importing from the PDB database, making this server (https://nciweb.dsi.upmc.fr) accessible to scientists with limited experience in bioinformatics. A quick overview of this tool and concise instructions are presented, together with an illustrative application.

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.

Steric clash in real space: biphenyl revisited.

A textbook case of twisted structure due to hydrogen-hydrogen steric clash, the biphenyl molecule, has been studied in real space from a new perspective. Long-term discrepancies regarding the origin of the steric repulsion are now reconciled under the NCI (Non Covalent Interaction) method, which reflects in 3D the balance between attractive and repulsive interactions taking place in the region between the phenyl rings. The NCI method confirms that the steric repulsion does not merely come from the H-H interaction itself, but from the many-atom interactions arising from the Cortho-H region, therefore providing rigorous physical grounds for the steric clash. This method allows a continuous scan of all the subtle changes on the electron density on going from the planar to the perpendicular biphenyl structure. The NCI results agree with other topological approaches (IQA, ELF) and are in line with previous findings in the literature regarding controversial H-H interactions in steric clash situations: H-H interactions are attractive, but repulsion appears between (Cortho-H)(Cortho-H), raising the intraatomic energy of the ortho H. ELF is also used to support these conclusions. Indeed, deformations are observed in compressed basins that allow to visualize the intraatomic effect of steric repulsion. These results can be easily extrapolated to systems with similar topological features in which steric clash is claimed to be the reason for instability.

NCIPLOT4: Fast, Robust, and Quantitative Analysis of Noncovalent Interactions.

The NonCovalent Interaction index (NCI) enables identification of attractive and repulsive noncovalent interactions from promolecular densities in a fast manner. However, the approach remained up to now qualitative, only providing visual information. We present a new version of NCIPLOT, NCIPLOT4, which allows quantifying the properties of the NCI regions (volume, charge) in small and big systems in a fast manner. Examples are provided of how this new twist enables characterization and retrieval of local information in supramolecular chemistry and biosystems at the static and dynamic levels.

Proteasome versus Thioredoxin Reductase Competition as Possible Biological Targets in Antitumor Mixed Thiolate-Dithiocarbamate Gold(III) Complexes.

New mixed gold(III) derivatives with dithiocarbamate and thiolate ligands have been synthesized and characterized. They display high anticancer activity against colon cancer cell lines without affecting to differentiated enterocytes, high stability in phosphate-buffered saline solution, and resistance to gold reduction in the presence of reducing agents in the majority of the derivatives. Some of them show interaction with thioredoxin reductase as derived from in vitro analysis and computational studies. However, a competition between this enzyme and proteasome is detected in cells, which is corroborated by the determination of proteasomal chymotrypsin-like activity inhibition. In addition, some of these dithiocarbamate gold(III) derivatives reduce cell viability and proliferation by intrinsic apoptotic pathway, with changes in mitochondrial membrane potential, cytochrome c release and caspase-3 activation. Consequently, our results show new complexes with proteasome as possible target in colorectal cancer.