Revisiting van der Waals Radii: From Comprehensive Structural Analysis to Knowledge-Based Classification of Interatomic Contacts.

Weak noncovalent interactions are responsible for structure and properties of almost all supramolecular systems, such as nucleic acids, enzymes, and pharmaceutical crystals. However, the analysis of their significance and structural role is not straightforward and commonly requires model studies. Herein, we describe an efficient and universal approach for the analysis of noncovalent interactions and determination of van der Waals radii using the line-of-sight (LoS) concept. The LoS allows to unambiguously identify and classify the "direct" interatomic contacts in complex molecular systems. This approach not only provides an improved theoretical base to molecular "sizes" but also enables the quantitative analysis of specificity, anisotropy, and steric effects of intermolecular interactions.

Structure-Based Discovery and Bioactivity Evaluation of Novel Aurora-A Kinase Inhibitors as Anticancer Agents via Docking-Based Comparative Intermolecular Contacts Analysis (dbCICA).

Aurora-A kinase plays a central role in mitosis, where aberrant activation contributes to cancer by promoting cell cycle progression, genomic instability, epithelial-mesenchymal transition, and cancer stemness. Aurora-A kinase inhibitors have shown encouraging results in clinical trials but have not gained Food and Drug Administration (FDA) approval. An innovative computational workflow named Docking-based Comparative Intermolecular Contacts Analysis (dbCICA) was applied-aiming to identify novel Aurora-A kinase inhibitors-using seventy-nine reported Aurora-A kinase inhibitors to specify the best possible docking settings needed to fit into the active-site binding pocket of Aurora-A kinase crystal structure, in a process that only potent ligands contact critical binding-site spots, distinct from those occupied by less-active ligands. Optimal dbCICA models were transformed into two corresponding pharmacophores. The optimal one, in capturing active hits and discarding inactive ones, validated by receiver operating characteristic analysis, was used as a virtual in-silico search query for screening new molecules from the National Cancer Institute database. A fluorescence resonance energy transfer (FRET)-based assay was used to assess the activity of captured molecules and five promising Aurora-A kinase inhibitors were identified. The activity was next validated using a cell culture anti-proliferative assay (MTT) and revealed a most potent lead 85(NCI 14040) molecule after 72 h of incubation, scoring IC50 values of 3.5-11.0 µM against PANC1 (pancreas), PC-3 (prostate), T-47D and MDA-MB-231 (breast)cancer cells, and showing favorable safety profiles (27.5 µM IC50 on fibroblasts). Our results provide new clues for further development of Aurora-A kinase inhibitors as anticancer molecules.

Pancake Bonding: An Unusual Pi-Stacking Interaction.

A category of parallel π-stacking interaction, termed pancake bonding, is surveyed. The main characteristics are: the interaction occurs among radicals with highly delocalized π-electrons in their singly occupied molecular orbitals (SOMOs), the contact distances in the π-stacking direction are shorter than the typical van der Waals distances, and the stabilization obtained by the bonding combination of the SOMO orbitals leads to direct atom-to-atom overlap with strong orientational preferences. These atypical intermolecular interactions contain a component of electron sharing between the radicals that can be viewed as covalent-like. Pancake bonded dimers characteristically have low-lying singlet and triplet states and show characteristic interlayer vibrational modes. Pancake bonded aggregates serve as molecular components in many conducting and other functional organic materials. The role of van der Waals (vdW) interactions in pancake bonded dimers, chains, and other aggregates is different from closed shell vdW aggregates: here the Pauli repulsions reduce the attractive dispersion interaction significantly. Fluxionality between π- and σ-bonded aggregates often occur in the context of pancake bonding. Both experimental and computational aspects are reviewed.

Distinguishing crystallographic from biological interfaces in protein complexes: role of intermolecular contacts and energetics for classification.

BACKGROUND: Study of macromolecular assemblies is fundamental to understand functions in cells. X-ray crystallography is the most common technique to solve their 3D structure at atomic resolution. In a crystal, however, both biologically-relevant interfaces and non-specific interfaces resulting from crystallographic packing are observed. Due to the complexity of the biological assemblies currently tackled, classifying those interfaces, i.e. distinguishing biological from crystal lattice interfaces, is not trivial and often prone to errors. In this context, analyzing the physico-chemical characteristics of biological/crystal interfaces can help researchers identify possible features that distinguish them and gain a better understanding of the systems. RESULTS: In this work, we are providing new insights into the differences between biological and crystallographic complexes by focusing on "pair-properties" of interfaces that have not yet been fully investigated. We investigated properties such intermolecular residue-residue contacts (already successfully applied to the prediction of binding affinities) and interaction energies (electrostatic, Van der Waals and desolvation). By using the XtalMany and BioMany interface datasets, we show that interfacial residue contacts, classified as a function of their physico-chemical properties, can distinguish between biological and crystallographic interfaces. The energetic terms show, on average, higher values for crystal interfaces, reflecting a less stable interface due to crystal packing compared to biological interfaces. By using a variety of machine learning approaches, we trained a new interface classification predictor based on contacts and interaction energetic features. Our predictor reaches an accuracy in classifying biological vs crystal interfaces of 0.92, compared to 0.88 for EPPIC (one of the main state-of-the-art classifiers reporting same performance as PISA). CONCLUSION: In this work we have gained insights into the nature of intermolecular contacts and energetics terms distinguishing biological from crystallographic interfaces. Our findings might have a broader applicability in structural biology, for example for the identification of near native poses in docking. We implemented our classification approach into an easy-to-use and fast software, freely available to the scientific community from http://github.com/haddocking/interface-classifier .

Performance of HADDOCK and a simple contact-based protein-ligand binding affinity predictor in the D3R Grand Challenge 2.

We present the performance of HADDOCK, our information-driven docking software, in the second edition of the D3R Grand Challenge. In this blind experiment, participants were requested to predict the structures and binding affinities of complexes between the Farnesoid X nuclear receptor and 102 different ligands. The models obtained in Stage1 with HADDOCK and ligand-specific protocol show an average ligand RMSD of 5.1 Å from the crystal structure. Only 6/35 targets were within 2.5 Å RMSD from the reference, which prompted us to investigate the limiting factors and revise our protocol for Stage2. The choice of the receptor conformation appeared to have the strongest influence on the results. Our Stage2 models were of higher quality (13 out of 35 were within 2.5 Å), with an average RMSD of 4.1 Å. The docking protocol was applied to all 102 ligands to generate poses for binding affinity prediction. We developed a modified version of our contact-based binding affinity predictor PRODIGY, using the number of interatomic contacts classified by their type and the intermolecular electrostatic energy. This simple structure-based binding affinity predictor shows a Kendall's Tau correlation of 0.37 in ranking the ligands (7th best out of 77 methods, 5th/25 groups). Those results were obtained from the average prediction over the top10 poses, irrespective of their similarity/correctness, underscoring the robustness of our simple predictor. This results in an enrichment factor of 2.5 compared to a random predictor for ranking ligands within the top 25%, making it a promising approach to identify lead compounds in virtual screening.

Hetero-π-Dimers of Phenalenyls.

Homogeneous π-stacking dimers of phenalenyl and its derivatives have gained tremendous interest as components of conducting organic materials. For the first time, we investigate theoretically heterogeneous phenalenyl π-dimers. Key parameters, including charge transfer, interaction energy, singly occupied molecular orbital (SOMO) energy, and spin density, are studied with the help of density functional theory. We find that the amount of charge transfer between the two monomers in phenalenyl π-dimers correlates with the difference in the SOMO energies of the constituent monomers, where the SOMO energy plays the role of a monomer (group) electronegativity index. Charge transfer plays an important role in stabilizing the heterodimers while maintaining a significant diradicaloid character. For five heterodimers the interaction energy is found to be as large as -30 to -50 kcal mol(-1) . The presented correlation between the monomer SOMO energy levels and their stability can provide a simple predictive tool to design new highly stable π-stacking heterodimers.

Effects of protein engineering and rational mutagenesis on crystal lattice of single chain antibody fragments.

Protein crystallization is dependent upon, and sensitive to, the intermolecular contacts that assist in ordering proteins into a three-dimensional lattice. Here we used protein engineering and mutagenesis to affect the crystallization of single chain antibody fragments (scFvs) that recognize the EE epitope (EYMPME) with high affinity. These hypercrystallizable scFvs are under development to assist difficult proteins, such as membrane proteins, in forming crystals, by acting as crystallization chaperones. Guided by analyses of intermolecular crystal lattice contacts, two second-generation anti-EE scFvs were produced, which bind to proteins with installed EE tags. Surprisingly, although noncomplementarity determining region (CDR) lattice residues from the parent scFv framework remained unchanged through the processes of protein engineering and rational design, crystal lattices of the derivative scFvs differ. Comparison of energy calculations and the experimentally-determined lattice interactions for this basis set provides insight into the complexity of the forces driving crystal lattice choice and demonstrates the availability of multiple well-ordered surface features in our scFvs capable of forming versatile crystal contacts.

Innovative computer-aided methods for the discovery of new kinase ligands.

Recent evidence points to significant roles played by protein kinases in cell signaling and cellular proliferation. Faulty protein kinases are involved in cancer, diabetes and chronic inflammation. Efforts are continuously carried out to discover new inhibitors for selected protein kinases. In this review, we discuss two new computer-aided methodologies we developed to mine virtual databases for new bioactive compounds. One method is ligand-based exploration of the pharmacophoric space of inhibitors of any particular biotarget followed by quantitative structure-activity relationship-based selection of the best pharmacophore(s). The second approach is structure-based assuming that potent ligands come into contact with binding site spots distinct from those contacted by weakly potent ligands. Both approaches yield pharmacophores useful as 3D search queries for the discovery of new bioactive (kinase) inhibitors.

Likelihood of atom-atom contacts in crystal structures of halogenated organic compounds.

The likelihood of occurrence of intermolecular contacts in crystals of halogenated organic compounds has been analysed statistically using tools based on the Hirshfeld surface. Several families of small halogenated molecules (containing organic F, Cl, Br or I atoms) were analysed, based on chemical composition and aromatic or aliphatic character. The behaviour of crystal contacts was also probed for molecules containing O or N. So-called halogen bonding (a halogen making short interactions with O or N, or a π interaction with C) is generally disfavoured, except when H is scarce on the molecular surface. Similarly, halogen⋯halogen contacts are more rare than expected, except for molecules that are poor in H. In general, the H atom is found to be the preferred partner of organic halogen atoms in crystal structures. On the other hand, C⋯C interactions in parallel π-stacking have a high propensity to occur in halogenated aromatic molecules. The behaviour of the four different halogen species (F, Cl, Br, I) is compared in several chemical composition contexts. The analysis tool can be refined by distinguishing several types for a given chemical species, such as H atoms bound to O or C. Such distinction shows, for instance, that C-H⋯Cl and O-H⋯O are the preferred interactions in compounds containing both O and Cl.

High-pressure studies of palladium and platinum thioether macrocyclic dihalide complexes.

The mononuclear macrocyclic Pd(II) complex cis-[PdCl2([9]aneS3)] ([9]aneS3 = 1,4,7-trithiacyclo-nonane) converts at 44 kbar into an intensely coloured chain polymer exhibiting distorted octahedral coordination at the metal centre and an unprecedented [1233] conformation for the thioether ligand. The evolution of an intramolecular axial sulfur-metal interaction and an intermolecular equatorial sulfur-metal interaction is central to these changes. High-pressure crystallographic experiments have also been undertaken on the related complexes [PtCl2([9]aneS3)], [PdBr2([9]aneS3)], [PtBr2([9]aneS3)], [PdI2([9]aneS3)] and [PtI2([9]aneS3)] in order to establish the effects of changing the halide ligands and the metal centre on the behaviour of these complexes under pressure. While all complexes undergo contraction of the various interaction distances with increasing pressure, only [PdCl2([9]aneS3)] undergoes a phase change. Pressure-induced I...I interactions were observed for [PdI2([9]aneS3)] and [PtI2([9]aneS3)] at 19 kbar, but the corresponding Br...Br interactions in [PdBr2([9]aneS3)] and [PtBr2([9]aneS3)] only become significant at much higher pressure (58 kbar). Accompanying density functional theory (DFT) calculations have yielded interaction energies and bond orders for the sulfur-metal interactions.