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  • 1
    Electronic Resource
    Electronic Resource
    Modelling the interactions of protein side-chains (1995)
    Springer
    Molecular engineering 5 (1995), S. 89-105 
    Details
    ISSN: 1572-8951
    Keywords: Molecular modelling ; protein side-chains ; hydrogen bonding ; electrostatic energy ; distributed multipole analysis ; amino/aromatic interactions ; intermolecular perturbation theory
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The study of small model molecules containing the relevant functional groups can help us to understand the interactions between side-chains in proteins.Ab initio quantum chemical techniques allow the interactions between the model molecules to be studied with much greater accuracy than is possible for an entire protein, where the use of simple empirical potentials is the norm. In particular, the use ofab initio methods on model molecules permits us to incorporate the atom-atom anisotropic directionality of these interactions. We survey various methods of obtaining the components of theab initio interaction energy. These are then applied to three systems of biological interest. The first of these is the arginine/aspartate pair found in salt bridges, which involves hydrogen bonding between two charged species. Secondly, we look at the arginine/phosphotyrosine interaction found in complexes between SH2 domains and peptide ligands: here we find that the arginine/phosphate part of the interaction is energetically far more important than the arginine/aromatic part. Finally, we describe a detailed study of amino/aromatic interactions in proteins: ‘unconventional hydrogen bonds’ are found to be remarkably uncommon relative to stacked geometries, and the reasons for this are examined.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00999581
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  • 2
    Electronic Resource
    Electronic Resource
    The orientation of N-H...O=C and N-H...N hydrogen bonds in biological systems: How good is a point charge as a model for a hydrogen bonding atom? (1997)
    Springer
    Journal of computer aided molecular design 11 (1997), S. 479-490 
    Details
    ISSN: 1573-4951
    Keywords: Hydrogen bonds ; Distributed multipoles ; Electrostatic potential extrema
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In order to design new ligands for protein-binding sites of unknownstructure, it would be useful to predict the likely sites of hydrogenbonding of an unknown protein fragment to a known molecule. The positions ofmaxima and minima in the electrostatic potential at appropriate distancesfrom the van der Waals surface were calculated for various small molecules,nucleic acid bases, peptide units and amino acid side chains containinggroups which can form the biologically important N-H...O=C andN-H...N hydrogen bonds. Their ability to predict the positions of H andO/N in hydrogen bonded complexes, as predicted by optimising theelectrostatic interactions of pairs of such molecules constrained by themolecular shapes, was assessed. It is shown that extrema in theelectrostatic potential around the isolated molecules give worthwhilepredictions for the locations of hydrogen bonding partners. For moleculesbound by a single N-H...O=C hydrogen bond, the electrostatic maximumassociated with the H is usually less than 1 Å from an acceptor atom,while a C=O electrostatic minimum is generally less than 1.5 Å fromthe hydrogen bond proton. However, a significant number of hydrogen bondsform to the opposite lone pair from the electrostatic minimum, in which casethe separation is up to 3.3 Å. This reflects the broad electrostaticpotential well around a carbonyl oxygen between the lone pair directions.The model predicts when neighbouring atoms drastically change the hydrogenbonding characteristics of an N-H or C=O group. Although the geometries ofhydrogen bonded complexes are influenced by the other van der Waals contactsbetween the molecules, particularly multiple hydrogen bonds, theseinfluences are constant when considering hydrogen bonding to a specificuncharacterised binding site. Hence, the consideration of stericallyaccessible electrostatic extrema will be useful in the design of newligands.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007923124523
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  • 3
    Electronic Resource
    Electronic Resource
    The matching of electrostatic extrema: A useful method in drug design? A study of phosphodiesterase III inhibitors (1995)
    Springer
    Journal of computer aided molecular design 9 (1995), S. 33-43 
    Details
    ISSN: 1573-4951
    Keywords: Distributed multipoles ; Electrostatic similarity ; Relative binding orientation ; Phosphodiesterase inhibitors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary Ligands which bind to a specific protein binding site are often expected to have a similar electrostatic environment which complements that of the binding site. One method of assessing molecular electrostatic similarity is to examine the possible overlay of the maxima and minima in the electrostatic potential outside the molecules and thereby match the regions where strong electrostatic interactions, including hydrogen bonds, with the residues of the binding site may be possible. This approach is validated with accurate calculations of the electrostatic potential, derived from a distributed multipole analysis of an ab initio charge density of the molecule, so that the effects of lone pair and π-electron density are correctly included. We have applied this method to the phosphodiesterase (PDE) III substrate adenosine-3′,5′-cyclic monophosphate (cAMP) and a range of nonspecific and specific PDE III inhibitors. Despite the structural variation between cAMP and the inhibitors, it is possible to match three or four extrema to produce relative orientations in which the inhibitors are sufficiently sterically and electrostatically similar to the natural substrate to account for their affinity for PDE III. This matching of extrema is more apparent using the accurate electrostatic models than it was when this approach was first applied, using semiempirical point charge models. These results reinforce the hypothesis of electrostatic similarity and give weight to the technique of extrema matching as a useful tool in drug design.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00117276
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  • 4
    Electronic Resource
    Electronic Resource
    Relative binding orientations of adenosine A1 receptor ligands — A test case for Distributed Multipole Analysis in medicinal chemistry (1995)
    Springer
    Journal of computer aided molecular design 9 (1995), S. 44-54 
    Details
    ISSN: 1573-4951
    Keywords: DMA ; Multipoles ; Electrostatic potentials ; Molecular similarity ; Agonists ; Antagonists ; Adenosine receptor ; Binding site
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary The electrostatic properties of adenosine-based agonists and xanthine-based antagonists for the adenosine A1 receptor were used to assess various proposals for their relative orientation in the unknown binding site. The electrostatic properties were calculated from distributed multipole representations of SCF wavefunctions. A range of methods of assessing the electrostatic similarity of the ligands were used in the comparison. One of the methods, comparing the sign of the potential around the two molecules, gave inconclusive results. The other approaches, however, provided a mutually complementary and consistent picture of the electrostatic similarity and dissimilarity of the molecules in the three proposed relative orientations. This was significantly different from the results obtained previously with MOPAC AM1 point charges. In the standard model overlay, where the aromatic nitrogen atoms of both agonists and antagonists are in the same position relative to the binding site, the electrostatic potentials are so dissimilar that binding to the same receptor site is highly unlikely. Overlaying the N6-region of adenosine with that near C8 of theophylline (the N6-C8 model) produces the greatest similarity in electrostatic properties for these ligands. However, N6-cyclopentyladenosine (CPA) and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) show greater electrostatic similarity when the aromatic rings are superimposed according to the flipped model, in which the xanthine ring is rotated around its horizontal axis. This difference is mainly attributed to the change in conformation of N6-substituted adenosines and could result in a different orientation for theophylline and DPCPX within the receptor binding site. However, it is more likely that DPCPX also binds according to the N6-C8 model, as this model gives the best steric overlay and would be favoured by the lipophilic forces, provided that the binding site residues could accommodate the different electrostatic properties in the N6/N7-region. Finally, we have shown that Distributed Multipole Analysis (DMA) offers a new, feasible tool for the medicinal chemist, because it provides the use of reliable electrostatic models to determine plausible relative binding orientations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00117277
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  • 5
    Electronic Resource
    Electronic Resource
    Book Review: Molecular Modeling of Inorganic Compounds, Peter Comba and Trevor W. Hambley, VCH, Weinheim, 1995, 240 pp. £76.00, ISBN 3-527-29076-1 (1997)
    New York, NY [u.a.] : Wiley-Blackwell
    Applied Organometallic Chemistry 11 (1997), S. 458-458 
    Details
    ISSN: 0268-2605
    Keywords: Chemistry ; Industrial Chemistry and Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Hydrogen bonding of carbonyl, ether, and ester oxygen atoms with alkanol hydroxyl groups (1997)
    New York, NY [u.a.] : Wiley-Blackwell
    Journal of Computational Chemistry 18 (1997), S. 757-774 
    Details
    ISSN: 0192-8651
    Keywords: O(SINGLE BOND)H ··· O hydrogen bond ; intermolecular perturbation theory ; crystal structures ; directionality ; esters ; Chemistry ; Theoretical, Physical and Computational Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Computer Science
    Notes: An attractive way to study intermolecular hydrogen bonding is to combine analysis of experimental crystallographic data with ab initio - based energy calculations. Using the Cambridge Structural Database (CSD), a distributed multipole analysis (DMA)-based description of the electrostatic energy, and intermolecular perturbation theory (IMPT) calculations, hydrogen bonding between donor alkanol hydroxyl groups and oxygen acceptor atoms in ketone, ether, and ester functional groups is characterized. The presence and absence of lone pair directionality to carbonyl and ether or ester oxygens, respectively, can be explained in terms of favored electrostatic energies, the major attractive contribution in hydrogen bonding. A hydrogen bond in its optimum geometry is only slightly stronger when formed to a ketone group than to an ether group. Hydrogen bonds formed to carbonyl groups have similar properties in a ketone or ester, but the ester O2 differs from an ether oxygen due to various environmental effects rather than a change in its intrinsic properties. For (E)-ester oxygens, there are few hydrogen bonds found in the CSD because of the competition with the adjacent carbonyl group, but the interaction energies are similar to an ether. Hydrogen bonds to O2 of (Z)-esters are destabilized by the repulsive electrostatic interaction with the carbonyl group. The relative abundance of nonlinear hydrogen bonds found in the CSD can be explained by geometrical factors, and is also due to environmental effects producing slightly stronger intermolecular interaction energies for an off-linear geometry. © 1997 by John Wiley & Sons, Inc. J Comput Chem 18: 757-774, 1997
    Additional Material: 13 Ill.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Crystal structure predictions for acetic acid (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Journal of Computational Chemistry 19 (1998), S. 459-474 
    Details
    ISSN: 0192-8651
    Keywords: crystal structure prediction ; distributed multipoles ; molecular dynamics ; symmetry constraints ; Chemistry ; Theoretical, Physical and Computational Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Computer Science
    Notes: Possible crystal structures of acetic acid were generated, considering eight space groups and assuming one molecule in the asymmetric unit. Our grid-search method was compared with a Monte Carlo approach as implemented in the Biosym/MSI Polymorph Predictor. This revealed no sampling deficiencies. A large number of possible crystal structures were found (∼100 within only 5 kJ/mol), including the experimental structure. Energy minimizations were done with a united-atoms force field (GROMOS), an all-atoms force field (AMBER), and a potential that describes the electrostatic interactions with distributed multipoles (DMA). In all cases, the experimental structure had a low lattice energy. The number of hypothetical crystal structures was reduced considerably by removing space-group symmetry constraints, or by a primitive molecular dynamics shake-up. Nevertheless, sufficient structures of equal or lower energy compared with the experimental structure remained to suggest that other factors need to be considered for genuine structure prediction.   © 1998 John Wiley & Sons, Inc.   J Comput Chem 19: 459-474, 1998
    Additional Material: 8 Ill.
    Type of Medium: Electronic Resource
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