Conformations of Cycloheptadecane. A Comparison of Methods for Conformational Searching.

Transcription

1 Conformations of Cycloheptadecane. A Comparison of Methods for Conformational Searching. M. Saunders, K. Houk, Y.-D. Wu, W.C. Still, M. Lipton, G. Chang, W.C. Guida J. Am. Chem. Soc. 1990, 112, Systematic and Random searches in torsional and Cartesian space. Molecular Dynamics Distance Geometry (doesn t use Cartesian Coords distance matrix) Heptadecane 4,782,969 conformations (17 Carbons linear anti and gauche)

2 Conformational searching Cartesian coordinate search Move all atoms randomly Minimize energy Generates high energy, distorted structures. Best with simple force fields. Can generate very strange local minima C H H H H

3 Conformational searching Monte Carlo Dihedral search Rotate torsions (typically 120 ), minimize energy. 3 N possible rotations. MCMM (random), SUMM (systematic) Bonds and angles unaffected, low energy, easy to minimize Ring breaking or flipping algorithm needed

4 Variables 1. Random vs. Systematic 2. Conformational Space coverage Random walk (i.e. most recent structure) Use directed (with energy window) 3. Coordinate system Cartesian Torsional Distance geometry

5 Conclusions 1. MD and distance geometry significantly slower 2. Generating structures is quick, minimizing takes time. 3. Random methods are significantly faster than systematic ones.

6 C. Parish et al./journal of Molecular Graphics and Modelling 2002, 21,

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8 Conformational searching Low Mode search Calculate vibrations (IR), move along soft modes Slow to cross high barriers. Good for exhaustive search of local space

9 C. Parish et al./journal of Molecular Graphics and Modelling 2002, 21,

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12 C. Parish et al./journal of Molecular Graphics and Modelling 2002, 21,

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17 Steered Molecular Dynamics Isralewitz, B.; Gao, M.; Schulten, K. Current Opinion in Structural Biology, 2001, 11,

18 Activated MD Kalko, S.G.; Gelpi, J.L.; Orozco, M. J. Am. Chem. Soc. 2001, 123,

19 J. Bartol, P. Comba, M. Melter, M. Zimmer J. Comp. Chem. 1999, 20, F. Fedeles, M. Zimmer Inorg. Chem. 2001, 40, 1557.

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21 The structure of F430 HOOC O H 2 NOC Me A H HN B' B Me N N COOH Ni HOOC H H D N N H C H COOH O COOH

22 Faeber, G.; Keller, W.; Kratky, C.; Jaun, B.; Pfaltz, A. et al. Helv. Chim. Acta 1991, 74, 697.

23 Normal-Coordinate Structural Decomposition (NSD) Shelnutt, J.A. et al Chem. Soc. Rev. 1998, 27, 31.

24 Overlap of all the structures in the 3 largest clusters, planar (top), ruffled (middle), and saddled (bottom). F430M and F430 in MCR are singleton s Todd, L.N.; Zimmer, M. Inorg. Chem. 2002, 41, 6831

25 Figure 2 COOMe COOMe COOMe O N H H COOMe O N H 13 H COOMe O N H H 12 COOMe F epi-F430 12,13-diepi -F430 At thermodynamic equilibrium 4% native F430, 8% of 13-epi F430 and 88% of the most stable isomer 12,13-diepi F430 are found

26 Bioinorganic Molecular Mechanics COOCH 3 O H 2 NOC Me HN B Me N N COOCH 3 Ni N N H COOCH 3 H H COOCH 3 O COOCH 3 Bartol, J.; Comba, P.; Melter, M.; Zimmer, M. J. Comp. Chem. 1999, 20, 1549.

27 Overlap of MM minimized structure with 12,13-diepi-F430M crystal structure. Zimmer, M. J. Biomol. Struct. & Dyn. 1993, 11, 203.

28 F epi F430 12,13-diepi F430 Zimmer, M. J. Biomol. Struct. & Dyn. 1993, 11, 203.

29 Methyl Coenzyme-M Reductase Methyl Coenzyme-M Reductase is composed of 3 subunits and contains two molecules of cofactor F430

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32 Nitrile Hydratase in microorganisms/plants Nitrile Hydratase R C N + H 2 O O R NH 2 O amidase O R NH 2 R OH + NH 3

33 Nitrile hydratase substrates Acrylonitrile I Ioxynil N HO C N Cl I Br C N C N Cl Dichlobenzil Br Bromoxynil

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35 Superimposition of the representative structures from 6 clusters from the MC search of bromoxynil in the NHase. The channel residue the active site bound to bromoxynil are displayed.

36 Path taken by the substrate to the active site over a dynamics run of 200ps with a force constant of 0.01kcal/mol Å 2 between the acrylamide and the x,y,z coordinates of the NO. The channel residues, active site, Arg167α and Glu165α shown.

37 Firefly Luciferase

38 Phenylalanine Activating Domain Of Gramicidin Synthetase 1 In A Complex With Amp and Phenylalanine

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40 -Define hot sphere -Complete disordered loops. -Complete missing side chains -MCMM with ring closure -Procheck

41 PROCHECK v

42 -Define hot sphere -Complete disordered loops. -Complete missing side chains -MCMM with ring closure -Procheck -Remove solvent molecules in active site -Add preminimized luciferyl-amp -Positional MCMM with NMR restraints (substrate), dihedral MCMM of side-chains in hot-sphere -Flat bottom with half-widths of 1.0A.

43 Biochemistry, 1998, 37,

44 Biochemistry 1999, 38,

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