Significant Non-covalent Interactions Research Articles

Solvent effects and Raman enhancement during the adsorption of atrazine on pristine Ag, Au, Cu and mixed clusters

Investigation of the adsorption properties of a herbicide, atrazine (6-chloro-4-N-ethyl-2-N-propan-2-yl-1,3,5-triazine-2,4-diamine) (CPD) with Ag, Au, Cu and their mixed clusters are presented using density functional theory (DFT) analysis. With metal clusters, it is found that CPD forms stable clusters, the drug-cluster complexation energy is maximum in CPD-Au2Cu (−38.69 and −45.79 kcal/mol) in vacuum and aqueous phase in comparison with other clusters. Dipole moment of the CPD-metal systems is higher than that of CPD. Clustering of CPD with metal cages enhances the Raman signals due to surface enhanced Raman scattering (SERS) activity. The exothermic processes and fluctuations in entropy during the processes were altered for all clusters as a result of CPD adsorption to the cages, indicating a change to a more ordered structure. Wavefunction based analysis indicated that there are significant non-covalent interactions (NCIs) between the system and the metal clusters.

Identification of novel peptide inhibitors of Plasmodium falciparum dihydrofolate reductase (PfDHFR): molecular docking and MD simulation studies

The presence of drug-resistant variants of Plasmodium parasites within the population has presented a substantial obstacle to the eradication of Malaria. As a result, numerous research groups have directed their efforts towards creating new medication candidates that specifically target parasites. In this study, our main objective was to identify tri-peptide inhibitors for Plasmodium falciparum Dihydrofolate Reductase (PfDHFR) with the aim of finding a new peptide that exhibits superior binding properties compared to the current inhibitor, WR99210. In order to achieve this objective, a virtual library consisting of 8000 tripeptides was generated and subjected to computational screening against wild-type PfDHFR. The purpose of this screening was to discover the most effective binders at the active site. The four most optimal tripeptides identified (Trp-Trp-Glu, Trp-Phe-Tyr, Phe-Trp-Trp, Tyr-Trp-Trp) exhibited significant non-covalent interactions inside the active site of PfDHFR and had binding energies ranging from −9.5 to −9.0 kcal/mol and WR99210 had a binding energy of −6.2 kcal/mol. A 250 ns Molecular Dynamics (MD) simulation was performed to investigate the kinetic and thermodynamic characteristics of the protein-ligand complexes. The Root Mean Square Deviation (RMSD) values for the optimal tripeptides fell within the allowed range, indicating the stability of the ligands inside the protein complex. The Ki value for the most effective tripeptide was 0.3482 µM, whereas WR99210 had a Ki value of 1.02 µM. This article presents the initial discovery of peptide inhibitors targeting PfDHFR. In this text, we provide a comprehensive explanation of the interactions that occur between peptides and the enzyme. Communicated by Ramaswamy H. Sarma

(Invited) Computational Predictions of Site-Dependent Reactivities for Complex Reactions in Confinement

It is well known that the relatively high overpotentials for oxygen evolution reactions arise from similar binding energies for HO* and HOO* intermediates that tend to move in lockstep on different catalysts. A strategy to break this scaling limitation is through differential stabilization of the two intermediates by engineering the reaction environment. Nanoporous materials such as zeolites and metal-organic frameworks provide such a possibility through their well-defined pore space that presents microscopically tunable reaction environments. Yet the predictive understanding of catalytic actions in these heterogeneous catalysts requires the ability to describe not only the electronic structure at the active site, but also how the extended environment interacts with the reacting species through individually weak yet collectively significant non-covalent interactions. In this talk, we present a new computational procedure that couples quantum-chemical methods and forcefield-based sampling to enable a consistent calculation of local activation energies for articulated reactants. As a first application, we studied hydrocarbon reactions in four different zeolites and showed how the method allows for the estimation of transition-state entropy and for the systematic calculation of site-dependent activation energies. The latter can be used to derive rigorous ensemble-averaged barriers for comparison with experiments, as well as guiding future strategies for controlling Al distributions during zeolite synthesis.

2D-3D supramolecular systems assemblied from minoxidil and organic acids: Preparation, spectral, crystallographic characterization and Hirshfeld surface analysis

In this job eight new multicomponent crystalline systems (including 2 cocrystals + 5 salts) from active pharmaceutical ingredient (API) minoxidil (mnd) and organic acids were successfully prepared via the very common slow solution evaporation method and featured by the structural and spectral characterizations. In these systems the mnd and its partners were coupled through the NH···O/OH···O linkages which are authenticated to be the most frequent associates (created in all), even in the coexistence of the other underlying disruptive non-covalent linking fragments. Apart from the NH⋯O/OH···O H-bonds, the OH···N H-bonds were also set up in 1–5 and 7. Close inspection of the crystal pilings uncovered that under the help of an array of subsidiary O···C, O···O, O···N, Cl···O, N···Cl, CH2···C, CH···N, CH···O/CH2···O, CH2···Cl, CH···π/CH2···π, NH···π, O···π, CH···CH2/CH2···CH2 and π···π forces, the systems were stretched into 2D-3D motifs. Significant non-covalent interactions were calculated by means of the Hirshfeld surface analysis for understanding the noncovalent interactions which stabilized the crystal packings. Thanks to the delicate equilibrium of the multiple associates, the homo/hetero synthons or both were set up, here the general R22(8) graph has appeared with the highest frequency. This work verifies that careful check of the multicomponent systems comprised of various acids for a given API where multiplex molecular impacts struggle to dictate the material structures can engender rich and striking outcomes.

2D-3D supramolecular assemblies containing 2-amino-4,6-dimethoxypyrimidine and carboxylic acids: Preparation, crystallographic characterization, and Hirshfeld surface analysis

Eight crystals (1–8) derived from various substituted carboxylic acids of 2-pyrazinecarboxylic acid, 3,4-methylenedioxybenzoic acid, 4‑hydroxy-3-nitrobenzoic acid, 4‑chloro-2-nitrobenzoic acid, mandelic acid, 4-nitrophenylacetic acid, 3,4,5-trimethoxycinnamic acid, and itaconic acid and 2-amino-4,6-dimethoxypyrimidine (admpm) were prepared and identified, and further characterized thoroughly with single crystal X-ray diffraction (SCXRD), and elemental analysis techniques. The melting points were also measured. Significant non-covalent interactions were calculated by means of the Hirshfeld surface analysis. Among the eight crystals, proton transfer from the carboxylic acid to ring N of the pyrimidine has occurred only at 1, while the remaining ones 2–8 were co-crystals. It is obvious that the R22(8) ring motif occurs in all cases when a carboxyl unit interacts with a pyrimidine base. The present work surely indicates that there are two main associate modes between the 2-amino-4,6-dimethoxypyrimidine and the carboxylic acids, which regularly occur, linear heterotetramer (LHT), and cyclic heterotetramer (CHT). Here, LHT is dominant as it occurs in 5/8 frequency (at 3–4 and 6–8), CHT in 2/8 (at 1–2), with the remaining one structure (5) forming a heterodimer. The heterotrimer (HT) was not established in this test. Thus LHT is more stable than CHT and other synthons.

Synergistic antimicrobial activity, MD simulation studies and crystal structure of natural alcohol motif containing novel substituted cinnamates

A series of natural alcohols motif containing novel substituted cinnamates were developed and screened against five bacterial strains namely, Enterococcus faecal (E. faecalis), Escherichia coli (E. coli), Bacillus subtilis (B. subtilis), Pseudomonas aeruginosa (P. aeruginosa) and Klebsiella pneumonieae (K. pneumonieae). Among all cinnamates, YS17 was identified with 100% bacterial growth inhibition across the panel, except in E. faecalis with MIC values of 0.25 mg/mL against B. subtilis and P. aeruginosa whereas 0.125, 0.5 and 1 mg/mL against E. coli, K. pneumonieae and E. faecalis, respectively. The growth inhibitory property of YS17 was further validated by disk diffusion, synergistic study and in vitro toxicity assays. Interestingly, YS17 exhibits synergistic effect in combination with the standard drug Ampicillin (AMP). The single crystal structure analysis of YS4 and YS6 was also performed which reconfirmed their proposed structures. Molecular docking visualized significant non-covalent interactions between E. coli MetAP and YS17 and the structural and conformational changes were further analysed using MD simulation studies. Overall, the study provided a suitable core for further synthetic alterations for their optimization as an antibacterial agent. Communicated by Ramaswamy H. Sarma

On the Role of Noncovalent Ligand-Substrate Interactions in Au(I) Catalysis: An Experimental and Computational Study of Protodeauration.

A systematic study of protodeauration, a crucial step often found in gold catalysis, was performed using isolated vinyl gold(I) complexes. By varying substituents on gold complexes, we explore how their properties influence protodeauration. Phenols were employed as the proton source, and their substituents were also varied, providing insight through variation of their acidity. A linear Hammett correlation is identified for the series of substituted vinyl gold(I) complexes, while a nonlinear trend is found for the series of substituted phenols. Computationally, we reproduce our experimental observations and identify significant noncovalent interactions (NCIs) between the proton donor and vinyl gold(I) complexes. This finding is of particular importance for gold-catalyzed reactions as they often employ linear two-coordinate complexes where the site of the reaction is spatially remote from the ligand bound to gold. The NCIs between substrates and intermediates lead to a significant acceleration of the protodeauration step in this work, opening the door to alternative strategies in the field of gold catalysis.

Cluster formation between an oxadiazole derivative with metal nanoclusters (Ag/Au/Cu), graphene quantum dot sheets, SERS studies, and solvent effects

Interaction of an oxadiazole derivative, 5-(3,4-dimethoxyphenyl)-3-(3-methoxyphenyl)-1,2,4-oxadiazole (DPMO) with Ag/Au/Cu and graphene quantum dots with different solvents, is reported theoretically. The adsorption energy is maximum for the Cu6 cluster and minimum for the Ag6 cluster. The asymmetric charge redistribution between DPMO and M6s produces an improvement in dipole moment values. The decrease in energy gaps of complexes increased conductivity and metal clusters can be used as a drug sensor. The solvation energies are more negative in solvent media than in the gaseous media, indicating an enhancement in the solvent medium’s stability. Wave function studies show that there exist significant noncovalent interactions between metal clusters and oxadiazole that facilitate cluster formation. DPMO is found to form stable clusters with graphene which is evident from the enhancement of Raman activity of the system through SERS also enabling it for sensing DPMO in a mixture.

Evidence of significant non-covalent interactions in the solution of Levetiracetam in water and methanol

• Structure and conformational dynamics of levetiracetam reported. • Significant intermolecular forces found between the drug and water and methanol. • Local energy decomposition provides contribution to each type of interactions. • Solvent dynamics using ab initio molecular dynamics. • Implicit solvation studies reported. SV2A is a protein necessary for synaptic neurotransmitter release in the brain. Levetiracetam, an antiepileptic medication, binds to SV2A to produce its effects. To halt seizures, Levetiracetam slows down these electrical signals by reducing excitement or increasing inhibition. In this manuscript, we present the theoretical study of the solvation dynamics of this drug with different solvents. We have used for optimizations and other calculations: PBE0-D3/def2-TZVP method and basis set for NBO, NCI, and wavefunction studies; PBE0-D3/def2-TZVP and DLPNO-CCSD(T) for LED, MD, and bond energy of Levetiracetam and its complex with water and methanol. Levetiracetam can produce four fragments: pyrrolidinone, propyl, carbenoxy-, and amine in amide, and the bond (BDE) energy is 358.3581 kcal/mol. The compounds show significant non-covalent interactions with water and methanol. LED shows Levetiracetam with methanol having the lowest and most stable energy is −98.5818 kcal/mol. Levetiracetam with water has the highest energy is −83.6130 kcal/mol, so methanol is a more suitable solvent than water for Levetiracetam. The NBO explains the delocalization energies of electrons in Levetiracetam with solvents, and this assay supports the solvation studies of LED and AIMD assay. AIMD shows that Levetiracetam with water has the highest energy changes depending on time, going to a higher positive sign, and Levetiracetam with methanol has the lowest energy changes depending on time going to a lower positive sign. The implicit solvation assay also shows the same result as LED and AIMD. The solvated system free energy of Levetiracetam with methanol has the lowest dielectric energy (–23.2865 kcal/mol) than Levetiracetam with water system energy (–23.2421 kcal/mol).

Structural and Energetic Aspects of Entacapone-Theophylline-Water Cocrystal

Pharmaceutical cocrystals are currently gaining interest among the scientific community, due to their great potential for providing novel crystalline forms with superior properties such as solubility, dissolution rate, bioavailability, and stability. Robust computational tools are valuable tools in the rationalization of cocrystal formation, by providing insight into the intermolecular interactions of multicomponent molecular solids. In this study, various computational techniques based on charge density analysis were implemented to assess structural and energetical perspectives of the interactions responsible for the formation and stability of entacapone-theophylline-water (ETP-THP-water, 1:1:1). Significant non-covalent interactions (NCIs) were identified and evaluated by Hirshfeld surface analysis and density functional theory (DFT) computations, and three-dimensional networks (energy vector diagrams, lattice energy frameworks) were constructed, outlining the crucial stabilizing role of water and the dominance of π-π stacking interactions in the cocrystal. Furthermore, thermal dehydration studies confirmed the strong binding of water molecules in the crystal lattice, as expressed by the high activation energy.

Identifying potential inhibitors of biofilm-antagonistic proteins to promote biofilm formation: a virtual screening and molecular dynamics simulations approach.

Microbial biofilms play a critical role in environmental biotechnology and associated applications. Biofilm production can be enhanced by inhibiting the function of proteins that negatively regulate their formation. With this objective, an in silico approach was adopted to identify competitive inhibitors of eight biofilm-antagonistic proteins, namely AbrB and SinR (from Bacillus subtilis) and AmrZ, PDE (EAL), PslG, RetS, ShrA and TpbA (from Pseudomonas aeruginosa). Fifteen inhibitors that structurally resembled the natural ligand of each protein were shortlisted using ligand-based and structure-based virtual screening. The top four inhibitors obtained from molecular docking using Autodock Vina were further docked using SwissDock and DOCK 6.9 to obtain a consensus hit for each protein based on different scoring functions. Further analysis of the protein-ligand complexes revealed that these top inhibitors formed significant non-covalent interactions with their respective protein binding sites. The eight protein-ligand complexes were then subjected to molecular dynamics simulations for 30ns using GROMACS. RMSD and radius of gyration values of 0.1-0.4nm and 1.0-3.5nm, respectively, along with hydrogen bond formation throughout the trajectory indicated that all the complexes remained stable, compact and intact during the simulation period. Binding energy values between -20 and -77kJ/mol obtained from MM-PBSA calculations further confirmed the high affinities of the eight inhibitors for their respective receptors. The outcome of this study holds great promise to enhance biofilms that are central to biotechnological processes associated with microbial electrochemical technologies, wastewater treatment, bioremediation and the industrial production of value-added products.

Identification and structure–activity relationship (SAR) studies of carvacrol derivatives as potential anti-malarial against Plasmodium falciparum falcipain-2 protease

In an effort to develop a potent anti-malarial agent against Plasmodium falciparum, a structure-guided virtual screening using an in-house library comprising 652 compounds was performed. By docking studies, we identified two compounds (JMI-105 and JMI-346) which formed significant non-covalent interactions and fit well in the binding pocket of PfFP-2. We affirmed this observation by MD simulation studies. As evident by the biochemical analysis, such as enzyme inhibition assay, Surface Plasmon Resonance (SPR), live-cell imaging and hemozoin inhibition, JMI-105 and JMI-346 at 25 µM concentration showed an inhibitory effect on purified PfFP-2. JMI-105 and JMI-346 inhibited the growth of CQS (3D7; IC50 = 8.8 and 13 µM) and CQR (RKL-9; IC50 = 14.3 and 33 µM) strains of P. falciparum. Treatment with compounds resulted in defect in parasite growth and development. No significant hemolysis or cytotoxicity towards human cells was observed suggesting that these molecules are non-toxic. We pursued, structural optimization on JMI-105 and in the process, SAR oriented derivatives (5a-5l) were synthesized and evaluated for growth inhibition potential. JMI-105 significantly decreased parasitemia and prolonged host survival in a murine model with P. berghei ANKA infection. The compounds (JMI-105 and JMI-346) against PfFP-2 have the potential to be used as an anti-malarial agent.

Abstract PR10: Tri-complex inhibitors of the oncogenic, GTP-bound form of KRASG12C overcome RTK-mediated escape mechanisms and drive tumor regressions in vivo

Abstract RAS proteins are small GTPases that drive cell proliferation and survival when bound to GTP. Mutant RAS proteins are found in approximately one-third of human cancers, and exist predominantly in the GTP-bound state, leading to excessive downstream signaling via interaction with effectors such as RAF. A KRAS mutation in which glycine-12 is mutated to cysteine (KRASG12C) is found in 11-12% of non-small cell lung cancers. Recently, multiple potent, covalent inhibitors of KRASG12C have been reported that target the inactive, GDP-bound form of KRASG12C, and thus rely on the residual intrinsic hydrolysis of GTP to cycle KRASG12C proteins through the inactive, GDP-bound state. This mechanism is vulnerable to adaptive responses in cancer cells that can activate RAS by increasing upstream signaling and further increase the relative abundance of KRASG12C(GTP) over KRASG12C(GDP). An inhibitor that directly targets the active, GTP-bound form of KRASG12C would overcome this limitation. Drawing inspiration from natural products like cyclosporine and rapamycin, we have developed tri-complex inhibitors of KRASG12C(GTP) that promote a ternary complex between KRASG12C and the abundant immunophilin cyclophilin A (CypA). These sanglifehrin-inspired inhibitors exploit significant non-covalent interactions in the SWI/SWII region of KRAS combined with an electrophilic cysteine-targeted warhead to potently and irreversibly inhibit KRASG12C(GTP). The inhibitors selectively drive formation of KRASG12C-inhibitor-CypA ternary complexes that are sterically prevented from interacting with the RAS Binding Domain (RBD) of BRAF in biochemical studies. In cellular models, KRASG12C(GTP) inhibitors attenuate both RAS-MAPK signaling and cell viability in cancer cell lines bearing KRASG12C mutations, but not other mutations in RAS or other pathway oncoproteins. In vivo administration of a KRASG12C(GTP) inhibitor drives dose-dependent tumor regressions in the NCI-H358 KRASG12C NSCLC xenograft mouse model and is well-tolerated. Consistent with targeting the KRAS(GTP) state, inhibitory activity in vitro is unaffected by RTK activation, whereas the activity of first generation KRASG12C(GDP) inhibitors is significantly attenuated. In addition, proliferation of NCI-H358 and MIA PaCa-2 cells in vitro is suppressed for a significantly longer duration with KRASG12C(GTP) inhibitor treatment compared to KRASG12C(GDP) inhibitors. The combination of sub-maximal concentrations of a MEK inhibitor and a KRASG12C(GTP) inhibitor drove pronounced cell death. In contrast, the MEK and KRASG12C(GDP) inhibitor combination evoked a modest enhancement of the antiproliferative effects and does not cause cell death. Tri-complex inhibitors that target the active, GTP-bound form of KRAS thus represent a second generation of KRASG12C inhibitor. Chemical modulation of the non-covalent and covalent interactions of our tri-complex inhibitors provides an exciting opportunity to step beyond KRASG12C to target the GTP-bound state of additional RAS variants, and we demonstrate in vitro covalent inhibition of KRASG13C. By directly targeting active RAS-GTP, tri-complex inhibitors have the potential to overcome adaptive resistance mechanisms that emerge following inhibition of aberrant RAS-MAPK pathway activation. Citation Format: Christopher J Schulze, Alun Bermingham, Tiffany J Choy, James J Cregg, Gert Kiss, Abby Marquez, Denise Reyes, Mae Saldajeno-Concar, Caroline E Weller, Daniel M Whalen, Yu C Yang, Elena S Koltun, Robert J Nichols, Mallika Singh, David Wildes, Adrian L Gill, Richard L Hansen, Steve Kelsey, Mark A Goldsmith, Jacqueline A.M. Smith. Tri-complex inhibitors of the oncogenic, GTP-bound form of KRASG12C overcome RTK-mediated escape mechanisms and drive tumor regressions in vivo [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PR10. doi:10.1158/1535-7163.TARG-19-PR10

A combined molecular dynamics simulation and quantum mechanics study on the physisorption of biodegradable CBNAILs on h-BN nanosheets.

The nanoscopic structure of biodegradable choline-based naphthenic acid ionic liquids near the hexagonal boron-nitride (h-BN) surface was analyzed using quantum mechanics calculations and molecular dynamics simulations. The effects of the type of the ring (aliphatic or aromatic) and the size of the ring in the anion counterpart of the aliphatic ionic liquids (ILs) on the configurations, binding energies, orbital energies, density of states, charge transfer, and thermochemistry of adsorption of ILs on the h-BN surface were investigated. Also the significance of non-covalent interactions on the adsorption of ILs was disclosed from the quantum theory of atoms in molecule. The results of radial distribution functions, number density, and also charge density profiles showed the existence of a solid-like bottom layer in the vicinity of the surface. Angular distribution functions revealed that while the most probable orientation in aromatic anions is parallel to the h-BN sheet, the most probable orientation in aliphatic rings apparently is perpendicular to the surface. The mobility of cations and anions in the studied ILs with respect to the h-BN sheet was analyzed using their mean square displacements. For all ions near the surface, dynamics in the parallel direction were faster than those in the z-direction due to the structuring of the solid-like layer of ILs near the h-BN surface. Altogether, this study provides new insights into the physisorption of this new class of biodegradable ILs on h-BN nanosheets at the molecular level.

A gadolinium(III) complex: synthesis, structure, photophysical profile and its role in the degradation of nitroaromatics

The synthesis and structural characterization of a gadolinium(III) complex with phenanthroline and thiocyanate ligands have been accomplished. The X-ray crystal structure reveals that Gd(III) in a slightly distorted square anti-prism coordinated with four thiocyanate ions and two phenanthroline molecules; one phenanthroline is protonated which compensates the charge of Gd(III) center. The crystal structure shows chemically significant non-covalent interactions like hydrogen bonding involving the thiocyanate ligand and π–π interactions between uncoordinated phenanthrolinium and coordinated phen. Investigation on the intermolecular interactions and crystal packing via Hirshfeld surface analysis reveals that close contacts are mainly associated with weak interactions. The fingerprint plots demonstrate that these weak interactions are important for crystal packing. The Gd(III) complex shows photophysical activity. The compound is capable of degrading toxic pollutants like nitroaromatics and may have far reaching consequences for cleaning these toxic pollutants from industrial effluents.

Theoretical insights into M–SO bonds in transition metal-sulfur monoxide complexes [{N(SPMe2)2}2M(SO)] (M = Fe, Ru, Os): Assessment of density functionals and dispersion interactions

Geometry, electronic structure and bonding analysis of the sulfur monoxide complexes [{N(SPMe2)2}2M(SO)] (M=Fe, Ru, Os) have been investigated with the DFT, DFT-D3 and DFT-D3(BJ) methods using density functionals BP86, PW91, BLYP, PBE, revPBE, and TPSS. The BP86 and PBE optimized geometries of complex [{N(SPMe2)2}2Ru(SO)] are in good agreement with the reported experimental values. The Mayer and Gopinathan–Jug bond orders confirm the presence of M–SO and S–O multiple bond characters. Hirshfeld charge analysis shows transfer of electron density from metal fragments to antibonding π∗ orbital of SO ligand. Significant noncovalent interactions between metal fragment and SO ligand are observed in the studied sulfur monoxide complexes. Noncovalent M---O and S---SO interactions have been justified by molecular orbital analysis. The M–SO bond dissociation energies vary in the order Fe<Ru<Os and depends on the choice of density functionals. The BP86/D3(BJ) dispersion corrections add 38% to the bond dissociation energy of Fe–SO bond, while only 22% and 17% to Ru–SO and Os–SO bonds, respectively. The π-bonding contributions to the total M–SO bonds are relatively smaller (22.6–27.0%) than the σ-bonding contribution.

Meta-Hybrid Density Functional Theory Study of Adsorption of Imidazolium- and Ammonium-Based Ionic Liquids on Graphene Sheet

In this study, two types of ionic liquids (ILs) based on 1-butyl-3-methylimidazolium [Bmim]+ and butyltrimethylammonium [Btma]+ cations, paired to tetrafluoroborate [BF4]−, hexafluorophosphate [PF6]−, dicyanamide [DCA]−, and bis(trifluoromethylsilfonyl)imide [Tf2N]− anions, were chosen as adsorbates to investigate the influence of cation and anion type on the adsorption of ILs on the graphene surface. The adsorption process on the graphene surface (circumcoronene) was studied using M06-2X/cc-pVDZ level of theory. Empirical dispersion correction (D3) was also added to the M06-2X functional to investigate the effects of dispersion on the binding energy values. The graphene···IL configurations, binding energies, and thermochemistry of IL adsorption on the graphene surface were investigated. Orbital energies, charge transfer behavior, the influence of adsorption on the hydrogen bond strength between cation and anion of ILs, and the significance of noncovalent interactions on the adsorption of ILs on the graph...

Rhenium(II) nitrosyl complexes: synthesis, characterization, DFT calculations and DNA nuclease activity

The rhenium(II) dinitrosyl and mononitrosyl complexes, i.e. [Re(NO)2(CN)4]·(Phen)2·2H2O (1) and PhenH[Re(NO)(CN)4(H2O)]·(Phen)·3H2O (2) have been isolated and characterized. The X-ray crystal structure of 2 reveals that Re(II) is octahedrally coordinated with one nitrosyl, four cyanides, and one water, with one phenanthroline protonated to compensate the charge of the Re(II) center. The crystal structure shows chemically significant non-covalent interactions like hydrogen bonding involving the uncoordinated water and π–π interactions between phenanthrolinium and phen. The structures of both complexes have been optimized by DFT. Absorption and emission spectral studies and viscosity measurements indicate that both 1 and 2 interact with calf thymus DNA through partial intercalation of DNA bases. The intrinsic-binding constants, obtained from UV–vis spectroscopic studies, are 1.2 × 104 and 7.2 × 104 M−1 for 1 and 2, respectively. Both 1 and 2 are capable of inducing cleavage of plasmid DNA in the presence of H2O2 to form the supercoiled form to nicked circular form. The spectroscopic results of DNA binding are supported by molecular docking studies.

Investigating macromolecular complexes using top-down mass spectrometry.

MS has emerged as an important tool to investigate noncovalent interactions between proteins and various ligands (e.g. other proteins, small molecules, or drugs). In particular, ESI under so-called "native conditions" (a.k.a. "native MS") has considerably expanded the scope of such investigations. For instance, ESI quadrupole time of flight (Q-TOF) instruments have been used to probe the precise stoichiometry of protein assemblies, the interactions between subunits and the position of subunits within the complex (i.e. defining core and peripheral subunits). This review highlights several illustrative native Q-TOF-based investigations and recent seminal contributions of top-down MS (i.e. Fourier transform (FT) MS) to the characterization of noncovalent complexes. Combined top-down and native MS, recently demonstrated in "high-mass modified" orbitrap mass spectrometers, and further improvements needed for the enhanced investigation of biologically significant noncovalent interactions by MS will be discussed.

Extension of the B3LYP–dispersion-correcting potential approach to the accurate treatment of both inter- and intra-molecular interactions

We recently demonstrated that dispersion-correcting potentials (DCPs), which are atom-centered Gaussian-type functions that were developed for use with B3LYP (Torres and DiLabio in J Phys Chem Lett 3:1738–1744, 2012), greatly improved the ability of the underlying functional to predict non-covalent interactions. However, the recent application of the B3LYP–DCP approach to study the β-scission of the cumyloxyl radical led to a calculated barrier height that was over-estimated by ca. 8 kcal/mol. We demonstrate in the present work that the source of this error arises from the previously developed carbon atom DCPs, which erroneously alters the electron density in the C–C covalent-bonding region. In this work, we developed a new C-DCP with a form that was expected to less strongly influence the electron density in the covalent bonding region. Tests of the new C-DCP, in conjunction with previously published H-, N-, and O-DCPs, with B3LYP–DCP/6-31+G(2d,2p) on the S66, S22B, HSG-A, and HC12 databases of non-covalently interacting dimers showed that it is one of the most accurate methods available for treating intermolecular interactions, giving mean absolute errors (MAEs) of 0.19, 0.27, 0.16, and 0.18 kcal/mol, respectively. Additional testing on the S12L database of very large complexation systems gave an MAE of 2.6 kcal/mol, demonstrating that the B3LYP–DCP/6-31+G(2d,2p) approach to be one of the best-performing and most feasible methods for treating large systems containing significant non-covalent interactions. Finally, we showed that the modeling of C–C-making/C–C-breaking chemistry is well predicted using the newly developed DCPs. In addition to predicting a barrier height for the β-scission of the cumyloxyl radical, that is, within 1.7 kcal/mol of the high-level value, application of B3LYP–DCP/6-31+G(2d,2p) to 10 databases that include reaction barrier heights and energies, isomerization energies, and relative conformation energies gives performance that is among the best of all available dispersion-corrected density-functional theory approaches.