Showing papers in "Journal of the American Chemical Society in 1988"

The OPLS [optimized potentials for liquid simulations] potential functions for proteins, energy minimizations for crystals of cyclic peptides and crambin.

Abstract: A complete set of intermolecular potential functions has been developed for use in computer simulations of proteins in their native environment. Parameters are reported for 25 peptide residues as well as the common neutral and charged terminal groups. The potential functions have the simple Coulomb plus Lennard-Jones form and are compatible with the widely used models for water, TIP4P, TIP3P, and SPC. The parameters were obtained and tested primarily in conjunction with Monte Carlo statistical mechanics simulations of 36 pure organic liquids and numerous aqueous solutions of organic ions representative of subunits in the side chains and backbones of proteins. Bond stretch, angle bend, and torsional terms have been adopted from the AMBER united-atom force field. As reported here, further testing has involved studies of conformational energy surfaces and optimizations of the crystal structures for four cyclic hexapeptides and a cyclic pentapeptide. The average root-mean-square deviation from the X-ray structures of the crystals is only 0.17 A for the atomic positions and 3% for the unit cell volumes. A more critical test was then provided by performing energy minimizations for the complete crystal of the protein crambin, including 182 water molecules that were initially placed via a Monte Carlo simulation. The resultant root-mean-square deviation for the non-hydrogen atoms is still ca. 0.2 A and the variation in the errors for charged, polar, and nonpolar residues is small. Improvement is apparent over the AMBER united-atom force field which has previously been demonstrated to be superior to many alternatives. Computer simulations are undoubtedly destined to became an increasingly important means for investigating the structures and dynamics of biomolecular systems.' At the heart of such theoretical calculations are the force fields that describe the interatomic interactions and the mechanics of deformations of the molecules.* There is also little doubt that there will be a continual evolution in force fields with added complexity and improved performance paralleling the availability of computer resources. Our own efforts in this area over the last few years have resulted in the OPLS potential functions for proteins whose development and performance are summarized here. These potential functions have a simple form and they have been parametrized directly to reproduce experimental thermodynamic and structural data on fluids. Consequently, they are computationally efficient and their description of proteins in solution or crystalline environments should be superior to many alterantives that have been developed with limited condensed-phase data. The latter point is pursued here primarily through calculations on the crystal structures for four cyclic hexapeptides, a cyclic pentapeptide, and the protein crambin. Improvements are apparent in comparison to the AMBER united-atom force field3 which has previously been shown to be superior to many alternative^.^ (1) Beveridge, D. L., Jorgensen, W. L., Eds. Ann. N.Y. Acad. Sci. 1986, 482. ( 2 ) For reviews, see: (a) Levitt, M. Annu. Reu. Biophys. Eioeng. 1982, 11, 251. (b) McCammon, J. A. Rep. Prog. Phys. 1984, 47, 1. (3) Weiner, S. J.; Kollman, P. A.; Case, D. A,; Singh, U. C.; Ghio, C.; Alagona, G.; Profeta, S.; Weiner, P. J. Am. Chem. SOC. 1984, 106, 765. Parametrization The peptide residues of proteins contain readily identifiable organic subunits such as amides, hydrocarbons, alcohols, thioethers, etc. In view of this and since data are available on the corresponding pure organic liquids, our approach to developing a force field for proteins was to build it up from parameters demonstrated to yield good descriptions of organic liquids. U1timately, the force field would need to treat both intramolecular terms for bond stretches, angle bends, and torsions, as well as the intermolecular and intramolecular nonbonded interactions. The latter are generally accepted to be the most difficult part of the problem and have been our focus.3 A simple, computationally efficient form was chosen to represent the nonbonded interactions through Coulomb and Lennard-Jones terms interacting between sites centered on nuclei (eq 1). Thus, the intermolecular inter-

Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins.

Abstract: Comparative molecular field analysis (CoMFA) is a promising new approach to structure/activity correlation. Its characteristic features are (1) representation of ligand molecules by their steric and electrostatic fields, sampled at the intersections of a three-dimensional lattice, (2) a new ‘field fit” technique, allowing optimal mutual alignment within a series, by minimizing the RMS field differences between molecules, (3) data analysis by partial least squares (PLS), using cross-validation to maximize the likelihood that the results have predictive validity, and (4) graphic representation of results, as contoured three-dimensional coefficient plots. CoMFA is exemplified by analyses of the affinities of 21 varied steroids to corticosteroidand testosterone-binding globulins. Also described are the sensitivities of results to the nature of the field and the definition of the lattice and, for comparison, analyses of the same data using various combinations of other parameters. From these results, a set of ten steroid-binding affinity values unknown to us during the CoMFA analysis were well predicted. A major goal in chemical research is to predict the behavior of new molecules, using relationships derived from analysis of the properties of previously tested molecules. Relationships derived primarily by empirical analysis of a data table, whose columns are numerical property values and whose rows are compounds, usually taking the form of a linear equation, are called quantitative structure/activity relationships (QSAR).I Especially in biological applications, it has long been agreed that the most relevant numerical property values would be shape-dependent. Work on comparative molecular field analysis (CoMFA) began 12 years ago with two additional observations: (1) at the molecular level, the interactions which produce an observed biological effect are usually non-covalent; and ( 2 ) molecular mechanics force fields, most of which treat noncovalent (non-bonded) interactions only as steric and electrostatic forces, can account precisely for a great variety of observed molecular properties.2 Thus it seems reasonable that a suitable sampling of the steric and electrostatic fields surrounding a set of ligand (drug) molecules might provide all the information necessary for understanding their observed biological properties. However, the emergence of a practical CoMFA methodology had to await a new method of data analysis, partial least squares (PLS),3 which can derive robust linear equations from tables having many more columns than rows, and a number of advances in the methodology of molecular graphics. Other “3D-QSAR” methodologies have been described. The molecular shape (MS) approaches, developed independently by Simon et aL4 and by H ~ p f i n g e r , ~ compare net, rather than location-dependent, differences in molecular connectivities, volumes, and/or fields. A second approach, the “distance geometry” method of Crippen,6 provides validation of a ”site-point” hypothesis, a list of binding set coordinates and properties that must be proposed by the investigator. A prototype version of the CoMFA method is called “DYLOMMS”.7 In related work, for exploring binding modes of ligands to receptors, Goodford* advocates the display of probe-interaction “grids”, similar to thme used in CoMFA, while Hansch, Blaney, Langridge, et aL9 have shown the complementarity of QSAR and molecular graphics in understanding enzyme inhibitor data. Below we describe the main features of the CoMFA approach, exemplifying its use by analyzing the binding affinities of 21 varied steroid structures to human corticosteroid-binding globulins (CBG) and testosterone-binding globulins10 (TBG). In this series, the comparative rigidity of the steroid nucleus allows the conformational variable to be neglected, and the in vitro, particularly simple, character of the test system minimizes the importance of nonreceptor-related, hence non-shape-related, compound differences on the experimental observations.” We then investigated the *Author to whom all correspondence should be addressed. 0002-7863/88/15 10-5959$01.50/0 sensitivity of the excellent results obtained to critical model assumptions. For the purpose of comparison, we have also analysed these steroid binding data using both classical and other ”molecular shape” parameters, in various combinations. Finally, toward the end of this work, we were informed of additional corticosteroid binding data,12 and thus were able to test the ability of our model to predict the binding constants of ten more, structurally diverse, steroids. Computational Methods CoMFA Methodology. The overall data flow of a CoMFA analysis appears in Figure I . Its top two panels show how the data table is constructed from the field values at the lattice intersections. These automatically calculated parameters are the energies of steric (van der Waals 6-12) and electrostatic (Coulombic, with a 1 / r dielectric) interaction between the compound of interest, and a “probe atom” placed at the various intersections of a regular three-dimensional lattice, large enough to surround all of the compounds in the series, and with a 2.0 A separation between lattice point unless otherwise stated. The van der Waals A / B values were taken from the standard Tripos force field” and the atomic charges were calculated by the method of Gasteiger and Mar~i l i . ’~ Unless stated otherwise, the probe atom had the van der Waals properties of sp3 carbon and a charge of +1.0. Wherever the prove atom experiences a steric repulsion greater than “cutoff“ (30 kcal/mol ( I ) Martin, Y. C. Quantitative Drug Design; Marcel Dekker: New York, 1978. (2) Burkert, U.; Allinger, N. L. Molecular Mechanics; American Chemical Society: Washington, DC, 1982. (3) Wold, S . ; Ruhe, A,; Wold, H.; Dunn, W. J., 111 SIAM J . Sci. Stat. Comput. 1984, 5 , 135. (4) Simon, Z.; Badileuscu, I.; Racovitan, T. J. Theor. Biol. 1977,66,485. Simon, Z . ; Dragomir, N.; Plauchithiu, M. G.; Holban, S . ; Glatt, H.; Kerek, F. Eur. J . Med. Chem. 1980, 15, 521. ( 5 ) Hopfinger, A. J. J . Am. Chem. SOC. 1980, 102, 7196. (6) Chose, A. K.; Crippen, G. M. J . Med. Chem. 1985, 28, 333 and references therein. (7) Cramer, R. D., 111; Milne, M. Abstracts of the ACS Meeting, April 1979, COMP 44. Wise, M.; Cramer, R. D.; Smith, D. M.; Exman, I. In Quantitative Approaches to Drug Design; Dearden, J. C., Ed.; Elsevier: Amsterdam, 1983; p 145. Wise, M. in Molecular Graphics and Drug Design; Burgen, A. S . V., Roberts, G. C. K., Tute, M. S., Elsevier: New York, 1986; pp 183-194. Cramer, R. D., 111; Bunce, J. D. In QSAR in Drug Design and Toxicology; Hadzi, D., Jerman-Blazic, B., Eds.; Elsevier: New York, 1987; P 3. (8) Goodford, P. J. J . Med. Chem. 1985, 28, 849. (9) Hansch, C.; Hathaway, B. A.; Guo, Z. R.; Selassie, C. D.; Dietrich, S . W.; Blaney, J. M.; Langridge, R.; Volz, K. W.; Kaufman, B. T. J . Med. Chem. 1984, 27, 129. (10) Dunn, J. F.; Nisula, B. C.; Rodbard, D. J . Clin. Endocrin. Metab. 1981, 63. ( I 1 ) Cramer, R. D., I11 Quant. Struct. Acf . Pharmacol., Chem. Biol. 1983, 2, 7, 13. Yunger, L. M.; Cramer, R. D., 111 Quant. Struc. Act. Relat. Pharmacol., Chem. Biol. 1983, 2, 149. (12) Westphal, U. Steroid-Protein Interactions I I ; Springer-Verlag: Berlin, 1986. ( 1 3) Vinter, J. G.; Davis, A.; Saunder, M. R. J . Comp-Aided Mol. Design 1987, 1, 31. (14) Gasteiger, J.; Marsili, M. Tetrahedron 1980, 36, 3219.

Directed reduction of .beta.-hydroxy ketones employing tetramethylammonium triacetoxyborohydride

Abstract: The mild reducing agent tetramethylammonium triacetoxyborohydride reduces acyclic P-hydroxy ketones to their corresponding anti diols with high diastereoselectivity. a-Alkyl substitution does not significantly affect the stereoselectivity of these reductions. In all cases examined, good to excellent yields of diastereomerically homogeneous diols were obtained. The mechanism of these reductions involves an acid-promoted ligand exchange of acetate for substrate alcohol by the triacetoxyborohydride anion. The resultant hydride intermediate, presumably an alkoxydiacetoxyborohydride, reduces proximal OH 0 OH OH 0 Me,NHB(OAc), Mew Me&OR - OR Me he

Surface derivatization and isolation of semiconductor cluster molecules

Abstract: Author(s): Steigerwald, ML; Alivisatos, AP; Gibson, JM; Harris, TD; Kortan, R; Muller, AJ; Thayer, AM; Duncan, TM; Douglass, DC; Brus, LE | Abstract: We describe a synthesis of nanometer-sized clusters of CdSe using organometallic reagents in inverse micellar solution and chemical modification of the surface of these cluster compounds. In particular we show how the clusters grow in the presence of added reagents and how the surface may be terminated and passivated by the addition of organoselenides. Passivation of the surface allows for the removal of the cluster molecules from the reaction medium and the isolation of organometallic molecules which are zinc blende CdSe clusters terminated by covalently attached organic ligands. Preliminary cluster characterization via resonance Raman, infrared, and NMR spectroscopy, X-ray diffraction, transmission electron microscopy, and size-exclusion chromatography is reported. © 1988, American Chemical Society. All rights reserved.

Asymmetric dihydroxylation via ligand-accelerated catalysis

Abstract: Dihydroxylation asymetrique de composes ethyleniques du type styrene, vinylcyclohexane, hexene-3 en les glycols correspondants

Very efficient visible light energy harvesting and conversion by spectral sensitization of high surface area polycrystalline titanium dioxide films

Abstract: Reference LPI-ARTICLE-1988-002doi:101021/ja00212a033View record in Web of Science Record created on 2006-02-21, modified on 2017-05-12

Lipase-catalyzed irreversible transesterifications using enol esters as acylating reagents: preparative enantio- and regioselective syntheses of alcohols, glycerol derivatives, sugars, and organometallics

Abstract: Lipase-catalyzed transesterification of the prochiral symmetric dialcohol (I) in an organic medium yields the optically active monoacetate (S)-(III) together with the diacetate (IV); the isopropenyl alcohol freed from (II) during the transesterification rapidly tautomerizes to volatile acetone, making the process irreversible and simpler for product isolation.

Highly enantioselective and substrate-selective polymers obtained by molecular imprinting utilizing noncovalent interactions. NMR and chromatographic studies on the nature of recognition

Abstract: Preparation de polymeres methacryliques hautement enantioselectifs et substrats selectifs par impression moleculaire de derives de la L-phenylalanine, selectivite gouvernee par les interactions entre le substrat et la phase stationnaire-polymere et par la nature des substituants de la phenylalanine. Etude chromatographique et RMN en faveur de l'existence de complexes multimoleculaires formes par liaisons electrostatique et hydrogene entre la phenylanilide et 3 monomeres methacryliques au maximum avant leur polymerisation

Vicinal diol cyclic sulfates. Like epoxides only more reactive

Abstract: Preparation de dioxyde-2,2 de dioxathiolannes-1,3,2(I) a partir de glycols et reactions des sulfates cycliques(I) avec divers nucleophiles (H − , N 3 − , F − , PhCO 2 − , NO 3 − , SCN − , PhCH 2 − )

Homogeneous asymmetric hydrogenation of functionalized ketones

Abstract: Hydrogenation asymetrique en alcool de diverses cetones (aminocetones, cetols, cetoesters, cetoamides, cetothioester, cetoethers, dicetones, cetoacide) catalysee par des complexes du ruthenium(II) et du bis-diphenylphosphino-2,2' binaphtyle-1,1'

Five-fold diamond structure of adamantane-1,3,5,7-tetracarboxylic acid

Abstract: Le compose du titre cristallise dans le systeme avec le groupe d'espace I4 1 /a et sa structure est affinee jusqu'a 0,051

13C CP/MAS NMR studies of amylose inclusion complexes, cyclodextrins, and the amorphous phase of starch granules: Relationships between glycosidic linkage conformation and solid-state 13C chemical shifts

Abstract: In order to characterize molecular conformations within starch granules and to examine the relationships between polysaccharide conformation and solid state 13C chemical shifts, a range of polymeric and oligomeric a-(1r4) glucans has been examined by cross polarization and magic angle spinning (CP/MAS) 13C NMR spectroscopy. Single helical amylose (polymeric a-(1r4) glucan) polymorphs with various molecular inclusions as well as a- and a-cyclodextrin hydrates have been studied and their 13C CP/MAS spectral features compared with those of both double helical and amorphous a-(1r4) glucans. Spectra of single helical amyloses show similar features irrespective of the nature of the included molecule and have only one resolved signal for each carbon site consistent with the nearly hexagonal packing of sixfold helices as characterized by X-ray diffraction. Cyclodextrin hydrates show resolved C-1 and C-4 resonances from each of the six (a-cyclodextrin) or seven (b-cyclodextrin) a-(1r4)-linked glucose residues present in the macrocycle. Chemical shift ranges in cyclodextrins are closely similar to those of single helical amyloses with the exception of one C-1 and one C-4 resonance in a-cyclodextrin which are at unusually high field and assigned to sites adjacent to a conformationally strained glycosidic bond. A comparison of solution chemical shifts with weighted averages of solid-state shifts suggests that b-cyclodextrin adopts glycosidic solution conformations similar to those found in the crystalline state but that a-cyclodextrin may be slightly more expanded in solution than in the crystalline state. Line widths in the a-(1r4) glucans studied can be rationalized in terms of crystalline perfection, and signal multiplicity arises through either intramolecular conformational effects (a- and b-cyclodextrin) or considerations of packing symmetry (double helical a-(1r4) glucans). The wide range of chemical shifts observed for C-1 and C-4 sites together with the essentially constant chemical shifts for other sites suggests that C-1 and C-4 chemical shifts are primarily determined by glycosidic linkage conformation. Correlations are found between C-1 chemical shifts and the sum of the moduli of the two torsion angles (p and p) describing rotation about the glycosidic bonds as well as with the modulus of p. Both correlations accurately predict the range and qualitatively predict the distribution of chemical shifts found for amorphous a-(1r4) glucans assuming the equiprobable occurrence of all allowed glycosidic conformations. Similarities in C-1 and C-4 chemical shifts for single helical amyloses and amorphous materials show that starch granule amorphous phases contain a significant fraction of single-helix-like local conformations. This observation is consistent with the presence of a-(1r4) glucan/lipid inclusion complexes within starch granules.