ParaFrag—an approach for surface-based similarity comparison of molecular fragments

A frequent task in computer-aided drug design is to identify novel chemotypes similar in activity but structurally different to a given reference structure. Here we report the development of a novel method for atom-independent similarity comparison of molecular fragments (substructures of drug-like molecules). The fragments are characterized by their local surface properties coded in the form of 3D pharmacophores. As surface properties, we used the electrostatic potential (MEP), the local ionization energy (IE_L), local electron affinity (EA_L) and local polarizability (POL) calculated on isodensity surfaces. A molecular fragment can then be represented by a minimal set of extremes for each surface property. We defined a tolerance sphere for each of these extremes, thus allowing us to assess the similarity of fragments in an analogous manner to classical pharmacophore comparison. As a first application of this method we focused on comparing rigid fragments suitable for scaffold hopping. A retrospective analysis of successful scaffold hopping reported for Factor Xa inhibitors [Wood MR et al (2006) J Med Chem 49:1231] showed that our method performs well where atom-based similarity metrics fail. Figure Encoding surface hotspots as a ParaFrag pharmacophore     

Molecular dynamics study of the initial stages of catalyzed single-wall carbon nanotubes growth: force field development

Effective force fields for Ni-C interactions developed by Yamaguchi and Maruyama for the formation of metallofullerenes are modified to simulate the catalyzed growth of single-wall carbon nanotubes on Ni_n clusters with n >20, and the reactive empirical bond order Brenner potential for C-C interactions is also revised to include the effect of the metal atoms on such interactions. Figure Force field parameters for carbon-metal interactions obtained from DFT calculations in small clusters.     

Electrostatic interactions play an essential role in DNA repair and cold-adaptation of Uracil DNA glycosylase

Life has adapted to most environments on earth, including low and high temperature niches. The increased catalytic efficiency and thermoliability observed for enzymes from organisms living in constantly cold regions when compared to their mesophilic and thermophilic cousins are poorly understood at the molecular level. Uracil DNA glycosylase (UNG) from cod (cUNG) catalyzes removal of uracil from DNA with an increased k_cat and reduced K_m relative to its warm-active human (hUNG) counterpart. Specific issues related to DNA repair and substrate binding/recognition (K_m) are here investigated by continuum electrostatics calculations, MD simulations and free energy calculations. Continuum electrostatic calculations reveal that cUNG has surface potentials that are more complementary to the DNA potential at and around the catalytic site when compared to hUNG, indicating improved substrate binding. Comparative MD simulations combined with free energy calculations using the molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) method show that large opposing energies are involved when forming the enzyme-substrate complexes. Furthermore, the binding free energies obtained reveal that the Michaelis-Menten complex is more stable for cUNG, primarily due to enhanced electrostatic properties, suggesting that energetic fine-tuning of electrostatics can be utilized for enzymatic temperature adaptation. Energy decomposition pinpoints the residual determinants responsible for this adaptation. Figure Electrostatic isosurfaces of cod uracil DNA glycosylase in complex with double stranded DNA     

Study of a ligand complexed with Cdk2/Cdk4 by computer simulation

Cyclin-dependent kinases (Cdks) play important roles in the regulation of the cell cycle. Their inhibitors have entered clinical trials to treat cancer. Very recently, Davis et al. (Nat Struct Biol 9:745–749, 2002) have found a ligand NU6102, which has a high affinity with cyclin-dependent kinase 2 (K _i =6 nM) but a low affinity with cyclin-dependent kinase 4 (K _i =1,600 nM). To understand the selectivity, we use homology modeling, molecular docking, molecular dynamics and free-energy calculations to analyze the interactions. A rational 3D model of the Cdk4–NU6102 complex is built. Asp86 is a key residue that recognizes NU6102 more effectively with Cdk2 rather than Cdk4. Good binding free energies are obtained. Energetic analysis reveals that van der Waals interaction and nonpolar contributions to solvent are favorable in the formation of complexes and the sulfonamide group of the ligand plays a crucial role for binding selectivity between Cdk2 and Cdk4. Figure Two-dimensional representative for the interacting model of NU6102 complexed with the Cdk4 from a predicted structure by LIGPLOT.      

Development of realistic models for Double Metal Cyanide catalyst active sites

Realistic molecular models of one and two-centre catalytic active sites originating from the cleavage of a precursor material known to give rise to an active double metal cyanide catalyst are described. Via periodic density functional calculations the structure of the proposed catalytic sites are shown to be dependent on electrostatic and structural relaxation processes occurring at the surfaces of the precursor material. It is shown how these effects may be adequately captured by small molecular models of the active sites. The general methodology proposed should provide a computationally efficient basis for detailed future studies into catalytic reactions over double metal cyanide materials. Figure Reconstructed DMC [100]-surface: electrostatic potential mapped on charge density isosurface This work has been originally presented on the Modelling and Design of Molecular Materials conference in Wrocław, Poland.     

Experimental and theoretical investigations of spectroscopic properties of azobenzene derivatives in solution

The UV-Vis spectra of series of polymethylmethacrylate (PMMA) copolymers with attached trans-azobenzene derivatives were measured in 1,1,2-trichloroethane. In order to gain some insight into the recorded spectra, the quantum chemical calculations were performed for the substituted azobenzenes using both configuration interaction with single excitations method (CIS) as well as density functional theory (DFT) with B3LYP and PBE0 functionals. The calculations were performed in solvent. In particular, we found that the PBE0 excitation energies are in very good agreement with the experimental data. Figure The plots of orbital contour surfaces for molecule II. The molecular orbitals were calculated at the PBE0/6-311++G(d,p) level of theory. The upper plot presents contour surface of HOMO and the lower presents contour surface of LUMO. Shown are the contour surfaces of orbital amplitude 0.04 (red) and -0.04 (blue)     

CHIH-DFT determination of the molecular structure infrared spectra,UV spectra and chemical reactivity of three antitubercular compounds: Rifampicin,Isoniazid and Pyrazinamide

Three of the most frequent antitubercular agents employed against Mycobacterium tuberculosis are: Rifampicin, Isoniazid and Pyrazinamide. It has been proven that the use of these antitubercular agents together, shortens the treatment period from 12–18 months to 6 months [1]. In this work we use a new Density Functional Theory chemistry model called CHIH-DFT (Chihuahua-Heterocycles-Density Functional Theory) that reflects the mixture of Hartree Fock exchange and DFT exchange, according to a mixing parameter based on empirical rules suited for heterocyclic systems. This new chemistry model was used to calculate the molecular structure of these antitubercular compounds, as well as their infrared, UV spectra, chemical reactivity and electronic properties. The UV and infrared spectra were obtained by experimental techniques. The calculated molecular structure, UV and IR spectra values from CHIH-DFT were compared with experimentally obtained values and theoretical studies. These results are in good agreement with experimental and theoretical studies. We also predicted using the relative electrophilicity and relative nucleophilicity concepts as defined by Roy et al. [2] the chemical active sites for the three antitubercular compounds as well as their electronegativity, ionization potential, electron affinity, hardness, dipole moment, E_HOMO-E_LUMO gap energy, etc.      

Alpha particle chemistry. On the formation of stable complexes between He2+ and other simple species: implications for atmospheric and interstellar chemistry

The possibility that stable complexes may be formed between alpha particles (He²⁺) and small molecules is investigated using QCISD quantum mechanical calculations. Implications for their presence in the terrestrial atmosphere and/or in interstellar space are discussed. Figure Optimized structure of a stable H₂OHe²⁺ complex     

Molecular electrostatic potentials in aromatic substituted 4-hydroxyquino-2-lones: Glycine/NMDA receptor antagonists

Hydroxyquinolone derivatives have proven to be useful for inhibition at the glycine binding site of N-methyl-D-aspartate (NMDA) receptor. In this work the electronic structure, molecular electrostatic potential (MESP) and vibrational characteristics of a set of C₃ substituted 4-hydroxyquino-2-lone (HQ) derivatives, which act as Glycine/NMDA receptor antagonists, have been investigated using the density functional calculations. In the optimized structures a substituent at the C₃ site of HQ tends to adopt a helical structure. MESP investigations reveal that the ligands showing better inhibition activity should possess electron-rich regions extending over the substituent and carbonyl group of HQ. A correlation of inhibitory activity to the molecular electrostatic potential topography at the carbonyl oxygen as well as to the molecular electron density topography turns out to be a significant output of the investigation. Figure Quantam chemical approach has been employed to understand the reactivity of a set of hydroxyquinolone derivatives known for their inhibition activity towards Glycine/NMDA receptor. Molecular electrostatic potential topography has been used as a tool to understand the reactivity pattern     

A theoretical investigation of cytotoxic activity of celastroid triterpenoids

Quantum chemical calculations at the B3LYP/6-31G* level of theory have been carried out on 20 celastroid triterpenoids to obtain a set of molecular electronic properties and to correlate these with cytotoxic activities. The cytotoxic activities of these compounds can be roughly correlated with electronic effects related to nucleophilic addition to C(6) of the compounds: The energies of the frontier molecular orbitals (E _HOMO and E _LUMO), the HOMO-LUMO energy gap, the dipole moment, the charge on C(6), and the electrophilicity on C(6). Figure LUMO of Pristimerin.     

Computer simulation of polypeptides in a confinement

A coarse-grained model of polypeptide chains confined in a slit formed by two parallel impenetrable surfaces was studied. The chains were flexible heteropolymers (polypeptides) built of two kinds of united atoms—hydrophobic and hydrophilic. The positions of the united atoms were restricted to the vertices of a [310] lattice. The force field consisted of a rigorous excluded volume, a long-distance potential between a pair of amino-acid residues and a local preference for forming secondary structure (helices). The properties of the chains were studied at a wide range of temperatures from good to bad solvent conditions. Monte-Carlo simulations were carried out using the algorithm based on the chain’s local changes of conformation and employing the Replica Exchange technique. The influence of the chain length, the distances between the confining surfaces, the temperature and the force field on the dimension and the structure of chains were studied. It was shown that the presence of the confinement chain complicates the process of the chain collapse to low-temperature structures. For some conditions, one can find a rapid decrease of chain size and a second transition indicated by the rapid decrease of the total energy of the system. Figure A scheme of a polypeptide chain built on a [310] lattice and confined to a slit formed by a pair of parallel impenetrable surfaces Proceedings of “Modeling Interactions in Biomolecules II,” Prague, September 5th–9th, 2005.     

Adsorption and phase transitions in adsorbed systems: structural properties of CCl<Subscript>4</Subscript> layers adsorbed on a graphite surface

We present the results of simulations of a CCl₄ monolayer adsorbed on a graphite surface. The CCl₄ molecule was represented either by a shapeless superatom or by its atomic sites. The simulations were carried out over a large range of temperatures, from 20 K up to 340 K. We address the following problems: (1) the influence of molecular shape on the structure and stability of phases (particularly at low temperatures), and (2) the influence of the graphite corrugation on layer stability and mechanism of phase transitions. In particular, we discuss the possibility and conditions of the appearance of hexatic phase in the system. Figure Temperature dependence of Φ6 order parameter for CCl₄ monolayer adsorbed onsmooth and corrugated surfaces, in the spherical Lennard Jones (LJ) approximation.For comparison, the order parameter calculated for MacDonald’s five-site potential is also presented     

Homology modeling and examination of the effect of the D92E mutation on the H5N1 nonstructural protein NS1 effector domain

Virulent H5N1 strains of influenza virus often harbor a D92E point mutation in the nonstructural protein NS1. This crucial mutation has been correlated with increased virulence and/or cytokine resistance, but the structural implications of such a change are still unclear. Furthermore, NS1 protein could also be a potential target for the development of novel antiviral agents against H5N1 strains. Therefore, a reasonable 3D model of H5N1 NS1 is important for the understanding of the molecular basis of increased virulence and the design of novel antiviral agents. Based on the crystal structure of a non-H5N1 NS1 protein, a model of H5N1 NS1 was developed by homology modeling, molecular mechanics and molecular dynamics simulations. It was found that the D92E mutation could result in weakened interactions of the carboxylate side chain with other phosphorylated residues, thereby activating phosphorylation of NS1. Figure Superposition of snapshots picked from the two molecular dynamic (MD) trajectories: a H5N1 NS1 homology model and b non-H5N1 NS1 crystal structure after 0 (green ribbon), 5 (blue ribbon) and 10 ns (pink ribbon) MD simulation     

Aromaticity and electronic properties of Heterosuperbenzene (Heterohexabenzocoronene)

A global electrophilicity parameter and the aromaticity of some heterocyclic polyaromatic hydrocarbons were evaluated on the basis of DFT calculations. The substitution of carbon atoms by nitrogen atoms dramatically changes the global electrophilicity of the molecules, with the fully substituted molecule being the most electrophilic with a reactivity very close to that of fullerene. Figure Fully substituted heterohexabenzocoronene Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

CHIH-DFT determination of the molecular structure and IR and UV spectra of solanidine

Solanidine is the steroidal aglycon of some potato glycoalkaloids and a very important precursor for the synthesis of hormones and some pharmacologically active compounds. In this work, we make use of a new chemistry model within Density Functional Theory, called CHIH-DFT, to calculate the molecular structure of solanidine, as well to predict its infrared and ultraviolet spectra. The calculated values are compared with the experimental data available for this molecule as a means of validation of our proposed chemistry model. Figure Molecular structure of solanidine calculated with the CHIH(small) model chemistry     

G2, G3, and complete basis set calculations on the thermodynamic properties of triazane

As a follow-up study to our study on tetrazane (N₄H₆), we present computed thermodynamic properties of triazane (N₃H₅). Calculated properties include optimized geometries, infrared vibrations, enthalpy of formation, enthalpy of combustion, and proton affinities. We have also mapped the potential energy surface as the molecule is rotated about the N-N bond. We have predicted a specific enthalpy of combustion for triazane of about -20 kJ g⁻¹. Figure Schematic diagram of the dielectric barrier discharge (left) and typical temporal profiles of voltage and current, as obtained from the simulations (right)     

Theoretical analysis of the effects of guanine oxidative damage on the properties of B-DNA telomere fragments

The molecular dynamics as well as ab initio MP2/6-31G(d = 0.25) single point calculations were performed for native and oxidized B-DNA telomeric fragments. The structural, dynamic, energetic and electrostatic properties along with frontier orbitals distribution were described for the central triad consisting of three guanine molecules in its canonical or oxidized forms. Although the average structural parameters characterizing all of the studied telomere fragments are close each to other, the significant consequence on angular and displacement flexibilities are observed. Namely, the increase of mutual displacement of two successive base pairs along either axis and increase of the rotation of two bases of opposite strand are main dynamic consequences of presence of 8-oxo-guanine in the central triad of telomeric B-DNA. Besides, the significant increase of stacking energies in case of 8-oxo-guanine were found. Furthermore, the guanine pattern visible from the major groove may be described as donor-acceptor-acceptor formed by H₈-N₇-O₆ atoms, respectively. To the contrary the presence of 8-oxo-guanine changes the electrostatic properties of the major groove into acceptor-donor-acceptor coming from O₈-H₇-O₆ atoms. This results in significant alteration of ESP characteristics. Finally, the molecular orbital properties are also significantly affected by oxidation of telomeric B-DNA fragments. All these factors contribute to decrease of binding of telomere proteins. Figure The consequences of guanine oxidation in central GGG telomeric triad on electrostatic properties of CCGTACTT-A₁G₂G₃G₄T₅T₆-AGGGTT-AACA telomere fragment Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

3D–QSAR studies of orvinol analogs as κ-opioid agonists

Orvinols are potent analgesics that target opioid receptors. However, their analgesic mechanism remains unclear and no significant preference for subtype opioid receptor has been achieved. In order to find new orvinols that target the κ-receptor, comparative 3D–QSAR studies were performed on 26 orvinol analogs using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The best predictions for the κ-receptor were obtained with the CoMFA standard model (q ²=0.686, r ²=0.947) and CoMSIA model combined steric, electrostatic, hydrophobic, and hydrogen bond donor/acceptor fields (q ²=0.678, r ²=0.914). The models built were further validated by a test set made up of seven compounds, leading to predictive r ² values of 0.672 for CoMFA and 0.593 for CoMSIA. The study could be helpful for designing and prepare new category κ-agonists from orvinols.      

Role of hydrophobic interactions and salt-bridges in β-hairpin folding

β-Hairpins are the simplest form of β-sheets which, due to the presence of long-range interactions, can be considered as tertiary structures. Molecular dynamics simulation is a powerful tool that can unravel whole pathways of protein folding/unfolding at atomic resolution. We have performed several molecular dynamics simulations, to a total of over 250 ns, of a β-hairpin peptide in water using GROMACS. We show that hydrophobic interactions are necessary for initiating the folding of the peptide. Once formed, the peptide is stabilized by hydrogen bonds and disruption of hydrophobic interactions in the folded peptide does not denature the structure. In the absence of hydrophobic interactions, the peptide fails to fold. However, the introduction of a salt-bridge compensates for the loss of hydrophobic interactions to a certain extent. Figure Model of b-hairpin folding: Folding is initiated by hydrophobic interactions (Brown circles). The folded structure, once formed, is stabilized by hydrogen bonds (red lines) and is unaffected by loss of hydrophobic contacts