Showing papers in "Journal of Molecular Graphics & Modelling in 1999"

Python: a programming language for software integration and development.

Abstract: One of the challenges in bio-computing is to enable the efficient use and inter-operation of a wide variety of rapidly-evolving computational methods to simulate, analyze, and understand the complex properties and interactions of molecular systems. In our laboratory we investigates several areas, including protein-ligand docking, protein-protein docking, and complex molecular assemblies. Over the years we have developed a number of computational tools such as molecular surfaces, phenomenological potentials, various docking and visualization programs which we use in conjunction with programs developed by others. The number of programs available to compute molecular properties and/or simulate molecular interactions (e.g., molecular dynamics, conformational analysis, quantum mechanics, distance geometry, docking methods, ab-initio methods) is large and growing rapidly. Moreover, these programs come in many flavors and variations, using different force fields, search techniques, algorithmic details (e.g., continuous space vs. discrete, Cartesian vs. torsional). Each variation presents its own characteristic set of advantages and limitations. These programs also tend to evolve rapidly and are usually not written as components, making it hard to get them to work together.

XCrySDen--a new program for displaying crystalline structures and electron densities.

Abstract: XCrySDen is a molecular and crystalline-structure visualization program, but its main function is as a property analyzer program. It can run on most UNIX platforms, without any special hardware or software requirements. Special efforts were made to allow for appropriate display of 3D isosurfaces and 2D contours, which can be superimposed on crystalline structure and interactively rotated and manipulated. XCrySDen is also a graphical user interface for the CRYSTAL95/98 (Saunders, V. R., et al. CRYSTAL98—User’s Manual. University of Torino, Turin, Italy, 1999) ab initio program and a visualization system for the WIEN97 (Blaha, P., et al. Comput. Phys. Commun. 1990, 59, 399) ab initio program. In this article the program functions are presented with a short description of the algorithms.

The whey acidic protein family: a new signature motif and three-dimensional structure by comparative modeling.

Abstract: Whey acidic proteins (WAP) from the mouse, rat, rabbit, camel, and pig comprise two "four-disulfide core" domains. From a detailed analysis of all sequences containing this domain, we propose a new PROSITE motif ([KRHGVLN]-X-?PF?-X-[CF]-[PQSVLI]-X(9,19)-C-?P?-X-[DN]-X-?N? -[CE]-X(5)-C-C) to accurately identify new four-disulfide core proteins. A consensus model for the WAP proteins is proposed, based on the human mucous proteinase inhibitor crystal structure. This article presents a detailed atomic model for the two-domain porcine WAP sequence by comparative modeling. Surface electrostatic potential calculations indicate that the second domain of the pig WAP model is similar to the functional human mucous proteinase inhibitor domains, whereas the first domain may be nonfunctional.

Toward minimalistic modeling of oral drug absorption.

Abstract: Poor intestinal permeability of drugs constitutes a major bottleneck in the successful development of candidate drugs. Fast computational tools to help in designing compounds with increased probability of oral absorption are required, since both medicinal and combinatorial chemists are under pressure to consider increasing numbers of virtual and existing compounds. The QSAR paradigm for drug absorption is expressed as a function of molecular size, hydrogen-bonding capacity, and lipophilicity. A nonlinear PLS model that can be achieved with minimal computational efforts is described. The QSAR model correlates human intestinal absorption (%HIA) data, and apparent Caco-2 cell permeability data, to parameters calculated from molecular structures. Two properties were found to be relevant for absorption predictions, namely H-bonding capacity, and hydrophobic transferability. The parsimony principle was applied in several aspects: single conformers were used to compute molecular surface areas; the definitions of "polar" and "nonpolar" surfaces were done in a simplistic fashion; simple and fast 2D descriptors were used to estimate other properties; the 1 PLS component model was selected. These choices result in a minimalistic model for oral absorption. The use of both %HIA and Caco-2 permeability data was found to stabilize and improve the model. This QSAR model can serve as a simple, quantitative extension of the "rule of five" scheme (Lipinski, C.A., Lombardo, F., Dominy, B.W., and Feeney, P.J. Adv. Drug Deliv. Rev. 1997, 23, 3-25), in a manner that can prove beneficial to the drug discovery process.

Investigation and modification of molecular structures with the nanoManipulator

Abstract: The nanoManipulator system adds a virtual reality interface to an atomic force microscope (AFM), thus providing a tool that enables the user not only to image but also to manipulate nanometer-sized molecular structures. As the AFM tip scans the surface of these structures, the tip–sample interaction forces are monitored, which in turn provide information about the frictional, mechanical, and topological properties of the sample. Computer graphics are used to reconstruct the surface for the user, with color or contours overlaid to indicate additional data sets. Moreover, by means of a force-feedback pen, which is connected to the scanning tip via software, the user can touch the surface under investigation to feel it and to manipulate objects on it. This system has been used to investigate carbon nanotubes, fibrin, DNA, adenovirus, and tobacco mosaic virus. Nanotubes have been bent, translated, and rotated to understand their mechanical properties and to investigate friction on the molecular level. AFM lithography is being combined with the nanoManipulator to investigate the electromechanical properties of carbon nanotubes. The rupture forces of fibrin and DNA have been measured. This article discusses how some of the graphics and interface features of the nanoManipulator made these novel investigations possible. Visitors have used the system to examine chromosomes, bacterial pili fibers, and nanochain aggregates (NCAs). Investigators are invited to apply to use the system as described on the web at http://www.cs.unc.edu/Research/nano/doc/biovisit.html.

VRDD: applying virtual reality visualization to protein docking and design.

Abstract: We have developed an interactive docking program called VRDD. It offers various modes of displaying molecules in an immersive, three-dimensional virtual reality (VR) environment. It allows a user to interactively perform molecular docking aided by automatic docking and side chain conformational search. Binding free energies are computed in real time, and the program enables the user to explore only clash-free orientations of a ligand. VRDD also supplies visual and auditory feedback during docking and side chain search, indicating the levels of atomic overlap and interaction energy. The stunning VR graphics immerse users in the scene and can maximally stimulate their design intuition. We have tested VRDD on three cases with increasing complexity: a nine-residue-long peptide bound to a major histocompatibility complex (MHC) molecule, barstar bound to barnase, and an antibody bound to a hemagglutinin. Without prior knowledge, combinations of hand-docking and automatic refinement led to accurate complex structures for the first two complexes. The third case, for which all automatic docking algorithms failed to identify the correct complex in a previous blind test, also failed for VRDD. Our results show that the combination of VR docking and automatic docking can make unique contributions to molecular modeling.

Molecular scaffold-based design and comparison of combinatorial libraries focused on the ATP-binding site of protein kinases.

Abstract: Compound libraries were designed to target specifically the ATP cofactor-binding site in protein kinases by combining knowledge- and diversity-based design elements. A key aspect of the approach is the identification of molecular building blocks or scaffolds that are compatible with the binding site and therefore capture some aspects of target specificity. Scaffolds were selected on the basis of docking calculations and analysis of known inhibitors. We have generated 75 molecular scaffolds and applied different strategies to compute diverse compounds from scaffolds or, alternatively, to screen compound databases for molecules containing these scaffolds. The resulting libraries had a similar degree of molecular diversity, with at most 12% of the compounds being identical. However, their scaffold distributions differed significantly and a small number of scaffolds dominated the majority of compounds in each library.

Rotational superposition: a review of methods.

Abstract: Rotational superposition is one of the most commonly used algorithms in molecular modelling. Many different methods of solving superposition have been suggested. Of these, methods based on the quaternion parameterization of rotation are fast, accurate, and robust. Quaternion parameterization-based methods cannot result in rotation inversion and do not have special cases such as co-linearity or co-planarity of points. Thus, quaternion parameterization-based methods are the best choice for rotational superposition applications.

The mean hydration of carbohydrates as studied by normalized two-dimensional radial pair distributions.

Abstract: The hydration of carbohydrates plays a key role in many biological processes. Molecular dynamics simulations provide an effective tool for investigating the hydration of complex solutes such as carbohydrates. In this article we devise an algorithm for the calculation of two-dimensional radial pair distributions describing the probability of finding a water molecule in a site defined by two reference atoms. The normalized 2D radial pair distribution is proposed as an effective tool for investigating and comparing localized or ordered water sites around flexible molecules such as carbohydrates when analyzing molecular dynamics simulations and the utility of 2D radial pair distributions is demonstrated using sucrose as an example. In this relatively simple structure, 2D radial pair distributions were able to characterize and quantify the importance of two unique interresidue hydration sites in which a water molecule is forming a bridge between the glycopyranosyl and fructofuranosyl residues. The approach is proposed to be a valuable tool for comparing and understanding the hydration of flexible biomolecules such as carbohydrates.

Combined quantum mechanical and molecular mechanical reaction pathway calculation for aromatic hydroxylation by p-hydroxybenzoate-3-hydroxylase

Abstract: The reaction pathway for the aromatic 3-hydroxylation of p-hydroxybenzoate by the reactive C4a-hydroperoxyflavin cofactor intermediate in p-hydroxybenzoate hydroxylase (PHBH) has been investigated by a combined quantum mechanical and molecular mechanical (QM/MM) method. A structural model for the C4a-hydroperoxyflavin intermediate in the PHBH reaction cycle was built on the basis of the crystal structure coordinates of the enzyme–substrate complex. A reaction pathway for the subsequent hydroxylation step was calculated by imposing a reaction coordinate that involves cleavage of the peroxide oxygen–oxygen bond and formation of the carbon–oxygen bond between the C3 atom of the substrate and the distal oxygen of the peroxide moiety of the cofactor. The geometric changes and the Mulliken charge distributions along the calculated reaction pathway are in line with an electrophilic aromatic substitution type of mechanism. The energy barrier of the calculated reaction is considerably lower when the substrate hydroxyl moiety is deprotonated, in comparison with the barrier found with a protonated hydroxyl moiety. This effect of the protonation state of the substrate on the calculated energy barrier supports experimental observations that deprotonation is required for hydroxylation of the substrate. A notable event in the calculated reaction pathway is a lengthening of the peroxide oxygen–oxygen bond at an intermediate stage. Further analysis of the reaction pathway indicates that this oxygen–oxygen bond elongation is accompanied by an increase in electrophilic reactivity on the distal oxygen of the peroxide moiety, which may assist the C–O bond formation in the reaction of the C4a-hydroperoxyflavin intermediate with the substrate. Analysis of the effect of individual active site residues on the reaction reveals a specific transition state stabilization by the backbone carbonyl moiety of Pro293. The crystal water 717 appears to drive the hydroxylation step through a stabilizing hydrogen bond interaction to the proximal oxygen of the C4a-hydroperoxyflavin intermediate, which increases in strength as the hydroperoxyflavin cofactor converts to the anionic (deprotonated) hydroxyflavin.

Computational prediction of the three-dimensional structures for the Caenorhabditis elegans tubulin family.

Abstract: In this article we characterize, from a structural point of view, all 16 members of the tubulin gene family of Caenorhabditis elegans (9 α-tubulins, 6 β-tubulins, and 1 γ-tubulin). We obtained their tertiary structures by computationally modifying the X-ray crystal structure of the pig brain α/β-tubulin dimer published by Nogales et al. [ Nature (London) 1998; 391 :199–203]. Our computational protocol involves changing the amino acids (with MIDAS; Jarvis et al., UCSF MIDAS . University of California, San Francisco, 1986) in the 3D structure of pig brain α/β-tubulin dimer followed by geometry optimization with the AMBER force field (Perlman et al., AMBER 4 . University of California, San Francisco, 1990). We subsequently analyze and compare the resulting structures in terms of the differences in their secondary and tertiary structures. In addition, we compare the pattern of hydrogen bonds and hydrophobic contacts in the guanosine triphosphate (GTP)-binding site for all members of the tubulin family. Our computational results show that, except for γ-tubulin, all members of the C. elegans tubulin family have similar secondary and 3D structures and that the change in the pattern of hydrogen bonds in the GTP-binding site may be used to assess the relative stability of different α/β-tubulin dimers formed by monomers of the tubulin family.

Binning schemes for partition-based compound selection

Abstract: Partition-based approaches to the selection of structurally diverse sets of compounds involve allocating compounds to the individual elements of a multidimensional grid that spans the available chemical space. The space is defined by an appropriate set of chemical properties, with subranges of the values of these properties being used to define the constituent elements, or bins. This article compares several binning schemes in terms of their ability to provide an even distribution of compounds across the available space and to maximise the numbers of active molecules identified in simulated assay experiments.

A Novel Approach to the Analysis of Substituent Effects. Quantitative Description of Ionization Energies and Gas Basicity of Amines.

Abstract: In this work, a new topological approach based on simple matrix algebra is introduced to explore substituent effects at the level of atomic additivity in the absence of significant resonance contributions. In the framework of the suggested method, all atoms are classified according to element and valence state. The sums of the inverse squared distances between the substituent atoms and the reaction centre of the molecule are used as operational parameters in the present method. The approach implies atomic level of consideration of inductive and steric effects and allows for quantification of substituent effects without the use of pre-established group substituent constants. The practical application of the model is illustrated by the quantitative interpretation of ionization energies and gas basicity of a broad range of amines. Further development of the elaborated approach is also discussed.

Three-dimensional pharmacophore hypotheses of octopamine receptor responsible for the inhibition of sex-pheromone production in Helicoverpa armigera

Abstract: Three-dimensional pharmacophore hypotheses were built on the basis of a set of nine octopamine (OA) agonists responsible for the inhibition of sex-pheromone production in Helicoverpa armigera . Of the 10 models generated by the program Catalyst/Hypo, hypotheses including hydrogen-bond acceptor (HBA), hydrophobic (Hp), and hydrophobic aliphatic (HpAl) features were considered important and predictive in evaluating OA agonists. An HBA and four hydrophobic features are the minimum components of an effective OA agonist-binding hypothesis, which resembles the results of binding activity to locust OAR3. Active agonists mapped well onto all of the features of the hypothesis, such as HBA, Hp, and HpAl features. On the other hand, inactive compounds lacking binding affinity were shown to be poorly capable of achieving an energetically favorable conformation shared by the active molecules in order to fit the 3D chemical feature pharmacophore models. Those hypotheses are considered useful in designing new leads for more active compounds. Further research on the comparison of models from agonists may help elucidate the mechanisms of OA receptor–ligand interactions.

Peptides quantitative structure-function relationships: an automated mutation strategy to design peptides and pseudopeptides from substitution matrices.

Abstract: The process by which analogs in peptide chemistry are currently designed does not include any quantitative basis for amino acid substitutions from pharmacological leads. Here, we show that substitution matrices such as PAM 250 can provide quantitative constraints compatible with biological activity. This article describes its use in a strategy of rational amino acid substitution in peptides and proteins: we have computed a chemically derived matrix equivalent to the well-known PAM 250 matrix, reflecting the natural mutability rates of amino acids in protein evolutions but that can be extended to all the noncoded amino acids. Some of these noncoded amino acids are widely used to mimic secondary structure, to constrain backbone conformation, or to evade protease degradation. An automated sequence mutation (ASM) strategy has been defined to generate mutations within constraints. Application of such a substitution matrix to quantitative structure–function relationship studies will be of use in the design of proteins and peptides destined to become pharmaceutical drugs. In particular, issues such as which functionally conserved substitutions are able to satisfy conformational restrictions, oral bioavailability, or formulation demands can be quantitatively addressed.

VisualiSAR: a web-based application for clustering, structure browsing, and structure-activity relationship study.

Abstract: VisualiSAR is a program designed to display chemical structures, find similarities and differences between them, and highlight relationships that might exist. The program integrates cluster analysis for the grouping of structurally related compounds, modal analysis of molecular fingerprints for the sorting and highlighting of chemical features, and a Web-based interface for flexibility and ease of use. VisualiSAR has proved useful for a number of applications including the discernment of structure-activity relationships (SAR) of high-volume screening data, and general structure browsing. This article discusses the design of the tool and illustrates two applications.

Schematic representation of residue-based protein context-dependent data: an application to transmembrane proteins.

Abstract: An algorithmic method for drawing residue-based schematic diagrams of proteins on a 2D page is presented and illustrated. The method allows the creation of rendering engines dedicated to a given family of sequences, or fold. The initial implementation provides an engine that can produce a 2D diagram representing secondary structure for any transmembrane protein sequence. We present the details of the strategy for automating the drawing of these diagrams. The most important part of this strategy is the development of an algorithm for laying out residues of a loop that connects to arbitrary points of a 2D plane. As implemented, this algorithm is suitable for real-time modification of the loop layout. This work is of interest for the representation and analysis of data from (1) protein databases, (2) mutagenesis results, or (3) various kinds of protein context-dependent annotations or data.

Solution conformation of phakellistatin 8 investigated by molecular dynamics simulations.

Abstract: Phakellistatin 8 is a cyclic decapeptide that inhibits cancer cell growth and has sequence and structure similar to antamanide. In molecular dynamics simulations of phakellistatin 8 in water, the decapeptide ring undergoes a conformational change from the saddle-like crystal structure to a more elongated conformation by a transition of the Tyr9 main chain from theaL to an extended structure. This is coupled to the loss of the NH9‐O6b-turn hydrogen bond and the transient dissociation of the Pro7‐Tyr9 side-chain packing. Furthermore, the water molecule acting as a transannular bridge forms an additional hydrogen bond with phakellistatin 8, namely with the NH group of Val5 besides those already present in the crystal structure, i.e., with the NH of Ile10 and the CO of Leu6. Thea-turn hydrogen bond between the Phe4 amide hydrogen and the Ile10 carbonyl oxygen is always present. The solution conformations of the two cyclic decapeptides are similar, in particular in the region involving the NH4‐O10 a turn of phakellistatin 8 and the NH5‐O1a turn of antamanide. The simulation results suggest that in aqueous solution the conformation of phakellistatin 8 is more extended than in the crystalline state, and on a nanosecond time scale phakellistatin 8 is more flexible than antamanide. © 1999 by Elsevier Science Inc.

Modeling glasses using the reverse Monte Carlo algorithm: addition of nuclear magnetic resonance and expanded coordination number constraints

Abstract: In simple oxide glasses the coordination number and oxidation state of the glass-forming element can be predicted directly from the “8 − n” rule. Tellurite glasses, however, are unusual in that the coordination number of oxygen around tellurium varies without a corresponding change in the oxidation state of tellurium. To model sodium tellurite glasses successfully using the reverse Monte Carlo algorithm several new constraints have been added. Changes include extending the original coordination constraint to allow multiple coordination numbers, and the addition of a new coordination constraint to keep the oxidation state of tellurium constant by limiting the number of bridging and nonbridging oxygens bonded to each tellurium atom. In addition, the second moment of the distribution of dipolar couplings for sodium atoms obtained from a spin-echo NMR experiment was added as a new constraint. The resulting real-space models are presented and the effectiveness of the new constraints is discussed.

Improved AMBER torsional parameters for the N-N rotational barrier in diacylhydrazines.

Abstract: The structure and rotational barrier for substituted diacylhydrazines are of significant interest given the role this functionality plays in peptidomimetics and ecdysone agonists, the latter of which have application as extremely selective insecticides. Ab initio calculations show that the lowest energy conformations are typically nonplanar with essentially perpendicular nitrogen lone pairs. Molecular mechanics calculations using the AMBER∗ force field in MacroModel yield minima and rotational barriers that are both quantitatively and qualitatively inconsistent with the ab initio results. In this work the AMBER∗ N-N rotational barriers for all configurations of the parent, methyl and di-methyl substituted diformylhydrazines have been fitted to MP2/6-31+G∗∗ relative energies. The resulting AMBER∗ torsional parameters have been validated by calculating the rotational barriers for N-t-butyl substituted diformylhydrazine, dibenzoylhydrazine and an azadipeptide. In each case the new AMBER∗ rotational barriers compare favorably with the corresponding MP2 calculated rotational barriers.

A homology modeling method of an icosahedral viral capsid: inclusion of surrounding protein structures.

Abstract: A methodological development is presented for homology modeling of an icosahedrally symmetric assembly of proteins. In the method, a main-chain structure of an asymmetric unit of a protein assembly is constructed and structure refinement is performed, taking the surrounding symmetry-related proteins into consideration with rotational symmetry boundary conditions. To test the procedure, three models of a poliovirus capsid were constructed with different modeling conditions based on the X-ray structure of a rhinovirus capsid. Model S and model N were constructed with and without considering surrounding proteins, respectively. Model N2 was obtained by refinement in rotational symmetry boundary conditions of the structure of model N. The three models were compared with the X-ray structure of a poliovirus capsid. Root mean square deviations and C α distances indicate that model S is the most accurate. Examination of the intermolecular short contacts indicates that model S and model N2 are superior to model N, because they do not make severe intermolecular short contacts. Symmetric intermolecular interactions are important for both the structural fragment search and energy minimization to predict better loop structures. The programs developed in this study are thus valuable in homology modeling of an icosahedral viral capsid.

The structure of electronic states in amorphous silicon.

Abstract: We illustrate the structure and dynamics of electron states in amorphous Si. The nature of the states near the gap at zero temperature is discussed and especially the way the structure of the states changes for energies ranging from midgap into either band tail (Anderson transition). We then study the effect of lattice vibrations on the eigenstates, and find that electronic states near the optical gap can be strongly influenced by thermal modulation of the atomic positions. Finally, we show the structure of generalized Wannier functions for amorphous Si, which are of particular interest for efficient ab initio calculation of electronic properties and forces for first principles dynamic simulation.

Identification, display, and use of symmetry elements in atomic and electronic structure models.

Abstract: Crystallographic symmetry plays an important role in structure determination from diffraction or scattering data, in spectroscopy and in simulations. It is convenient and insightful to integrate the display and use of such symmetry data with data analysis and modeling methods. We outline the integration of a suite of crystallographic algorithms, closely coupled with interactive graphical displays. These include techniques for identifying the unit cell of a solid, for automatically determining space and point group symmetries, for generalized displays of symmetry elements overlaid on structural models, and for construction, editing, and transformation of models subject to symmetry constraints. In addition, electron densities derived from periodic density functional calculations can be symmetrized and displayed with the corresponding symmetry elements. Applications of these various capabilities in crystallographic research are illustrated by topical examples.

Three-dimensional molecular field analyses of octopaminergic agonists and antagonists for the locust neuronal octopamine receptor class 3.

Abstract: The quantitative structure–activity relationship (QSAR) of a set of 70 octopaminergic agonists and 20 antagonists against octopamine receptor class 3 (OAR3) in locust nervous tissue was analyzed by molecular field analysis (MFA). MFA of these compounds evaluated effectively the energy between a probe and a molecular model at a series of points defined by a rectangular grid. Contour surfaces for the molecular fields are presented. These results provide useful information in the characterization and differentiation of octopaminergic receptor types and subtypes.

Full window stereo.

Abstract: Visualisation is the bioinformaticist’s most important tool for the study of macromolecules, and being able to see molecules in stereo is a crucial aspect. Stereo vision is based on the principle that each eye is presented with the best possible image of what it would have seen if the object was really there in 3D. The simplest approach to stereo vision is to display the right eye picture on the right half of the screen and the left eye picture on the left half while using a mirror system to ensure that each eye sees what it is supposed to see. More expensive workstations use hardware to alternately display the left and right eye pictures while synchronously blocking the transparency in the right or left lens of the special glasses worn by the user. We present here some simple software that uses inexpensive hardware, originally designed for the computer game industry, to make full screen stereo available on Linux-based PCs. The quality of the stereo vision is similar to the top-of-the-line graphics workstations that are capable of quad-buffering. This stereo option has been incorporated in the X11 based version of WHAT IF (Vriend, G. J. Mol. Graphics 1990, 8, 52–56), but the stereo source code is freely available and can easily be incorporated in other visualization packages.