MM3(96) CONFORMATIONAL ANALYSIS OF d-GLUCARAMIDE AND X-RAY CRYSTAL STRUCTURES OF THREE d-GLUCARIC ACID DERIVATIVES—MODELS FOR SYNTHETIC POLY(ALKYLENE d-GLUCARAMIDES)

An exhaustive conformational analysis of d-glucaramide was carried out using MM3(96) [MM3(96). Molecular Mechanics Software used with permission from N.L. Allinger; University of Georgia]. Nine torsion angles were each driven in increments of 120°, generating 19,683 starting conformations. Each conformation was then fully energy-minimized using MM3's block diagonal/full matrix optimization option at dielectric constants of both 3.5 and 6.5. Conformer populations were calculated based on the modeling results and calculated theoretical average ¹H vicinal coupling constants were compared to experimental values obtained in D ₂O solution. Crystal structures of three acyclic d-glucaric acid derivatives (N, N′-dimethyl- d-glucaramide, dipotassium d-glucarate, and sodium potassium d-glucarate) are reported. These structures and that of previously reported monopotassium glucarate correspond closely with model conformations that were within one kcal/mol of the global minimum.     

The peculiar conformational characteristics of cis-poly(tert-butlacetylene)

Molecular mechanics was applied to investigate the conformational structure of cis-poly(tert-butylacetylene) (c-PTBA). The program CHAMP, adopting a MM2-based force field, was used for a thorough search of the minimum-energy conformers of oligomers, helices and long segments of the c-PTBA chain. The results show that short oligomers are not good models of the polymer, as their preferred conformations are not allowed inside the chain. Segments of 8₃ and 8₅ helices appear as the most probable feature. Junctions between right- and left-handed helices can occur at the cost of 1,7 kcal/mol: such defects may run through the chain, the barrier to their shift being 7,8 kcal/mol. Other conformational defects, having energies in the range of 1–3 kcal/mol above the minimum, form knuckle-joints in the helix, changing the axial direction by 70–80°. The present calculations suggest a disordered model of c-PTBA in solution, made of rather stiff helical segments. Such a picture corresponds to a chain less rigid than proposed by previous computations on substituted polyacetylenes, and seems consistent with the observed physical aging of c-PTBA films. Preliminary packing calculations of right- and left-handed helices lead to density values not much higher than observed, indicating rather low degrees of disorder and free volume in the solid state.     

Stochastic searches for lactone and cycloalkene conformers

The stochastic search method coupled to MM3(92) has been used to locate as many conformers as possible for 6- to 11-membered ring lactones, trans-cycloalkenes, and cis-cycloalkenes. A comparison was carried out between the conformers of lactones and cycloalkenes of the same ring size for each force field. These comparisons were carried out by means of (1) conformational distances, defined as the rms deviation between the dihedral angles of the conformers being compared, and (2), substitution, in which a lactone was transformed into an olefin and vice versa, trying to keep as much as possible the initial geometry, followed by reoptimization. It is found that cycloalkenes and lactones share many common characteristics. The thermodynamic information provided by MM3 was used to study the dependence of conformer population upon (1) temperature and (2) total number of conformers. © 1993 John Wiley & Sons, Inc.     

Chair/Twist-Boat Energy Gap in Monocyclic, Conformationally Unconstrained Polyalkylcyclohexanes

A conformational search procedure (HUNTER), in combination with the MM3(92) program, was used for the exploration of the conformational hypersurface of alkyl-substituted cyclohexanes and for the calculation of their chair/twist-boat (TB) energy gap. The systems studied were conformationally unconstrained polyalkylcyclohexanes (alkyl = methyl, ethyl, isopropyl, and tert-butyl) possessing either geminal and/or vicinal arrangements of the alkyl groups, but differing in the number of alkyl substituents and in their relative disposition (i.e., cis or trans). The calculations indicate that in 1,1,3,3,5,5-hexaisopropylcyclohexane the TB is the lowest energy form. Modification of the cis,trans relationship of vicinal alkyl groups changes the chair/TB energy gap, and in the minimum energy conformation of cis,trans,trans-1,2,3,4-tetraisopropylcyclohexane (23c) and cis,syn,cis-1,2,4,5-tetraisopropylcyclohexane (31c) the cyclohexyl ring adopts a TB conformation. The tetrasubstituted systems cis,syn,cis-1,2-diisopropyl-3,4-dimethylcyclohexane (46), cis,syn,cis-1,4-diisopropyl-2,5-dimethyl-cyclohexane (47), and cis,trans,trans-1,2-diisopropyl-3,4-dimethylcyclohexane (41) are the least crowded monocyclic unconstrained cyclohexanes found in which the TB conformation is of lower energy than the chair form. The present study indicates that two methyls and two isopropyl substituents are sufficient for stabilizing the TB form of a cyclohexyl ring relative to the chair form.     

The application of molecular mechanics to the structures of carbohydrates

A study is reported of the accuracy with which the geometries of pyranose and methyl pyranoside molecules are predicted by molecular mechanics. Calculations of the conformational energies of the model compounds dihydroxymethane, methoxymethanol, and dimethoxymethane, made with the program MMI, produced results that compare well with previous ab initio molecular orbital calculations. This indicates that MMI gives a satisfactory account of the energetic and conformational aspects of the anomeric effect, a conclusion further supported by calculations on 2-methoxytetrahydropyran. The prediction of the observed preferred conformations of the primary alcohol group in aldohexopyranoses appears to be less satisfactory. MMI-CARB, a version of MMI with changes in some of the equilibrium C? O bond lengths of the program, has been used to calculate the geometries of 13 pyranose and methyl pyranoside molecules, the crystal structures of which have been studied by neutron diffraction. When the C? C? O? H torsion angles are constrained to approximately the values observed in the crystal structures, good agreement is obtained between the theoretical and experimental molecular geometries. The rms deviation for C? C and C? O bonds, excluding those significantly affected by thermal motion in the crystal structure determinations, is 0.005 Å. Corresponding figures for the valence angles that do not involve hydrogen atoms and for the ring torsion angles are 1.2° and 2.0°, respectively. The Cremer and Pople puckering parameters for the pyranose rings are reproduced within 0.026 Å in Q and 5.4° in θ.     

Molecular modeling studies of novel heteroarotinoids

The molecular structure and conformational properties of structurally related oxo and thio heteroarotinoids have been calculated by employing AM1 molecular orbital and both MM2P and Chem-X “optimize” molecular mechanics methods, and the results have been compared with crystal structure data. For the cis and trans oxo heteroarotinoids, MM2P gives values of the bridge torsion angles ?₁ and ?₂ in closest agreement with the crystal structure, and all three computational methods yield values of ?₁ and ?₂ within about 10° of that found in the crystal structures. All three computational methods locate a minimum-energy conformation for the trans isomer corresponding to the two bridged aryl rings being mutually perpendicular, in agreement with the crystal structure and similar to that found for the structurally analogous trans-stilbene. The calculated heteroring geometries also reproduce the twist-sofa conformation observed for the crystal structure. Calculated conformational energies versus ?₁ and ?₂ indicate broad energy wells about the minimum-energy conformation with barriers to rotation at the planar and perpendicular conformations, and with higher barriers found for the more sterically congested cis isomer. The corresponding cis and trans thio heteroarotinoids exhibit conformational properties similar to their oxo analogues. Both AM1 and MM2P fare poorly in reproducing the crystal structure values of the sulfur-containing bond lengths and bond angles. The C-S bonds found in these thio heteroarotinoids may possess more double-bond character than accounted for in the calculations. Also, the results suggest that the MM2P sulfur-related force-field parameters adopted for these calculations may require further refinement.     

Conformational analysis of the disaccharide methyl α‐d‐mannopyranosyl‐(1→3)‐2‐O‐acetyl‐β‐d‐mannopyranoside monohydrate

The crystal structure of methyl α‐d ‐mannopyranosyl‐(1→3)‐2‐O‐acetyl‐β‐d ‐mannopyranoside monohydrate, C₁₅H₂₆O₁₂·H₂O, ( II ), has been determined and the structural parameters for its constituent α‐d ‐mannopyranosyl residue compared with those for methyl α‐d ‐mannopyranoside. Mono‐O‐acetylation appears to promote the crystallization of ( II ), inferred from the difficulty in crystallizing methyl α‐d ‐mannopyranosyl‐(1→3)‐β‐d ‐mannopyranoside despite repeated attempts. The conformational properties of the O‐acetyl side chain in ( II ) are similar to those observed in recent studies of peracetylated mannose‐containing oligosaccharides, having a preferred geometry in which the C2—H2 bond eclipses the C=O bond of the acetyl group. The C2—O2 bond in ( II ) elongates by ～0.02 Å upon O‐acetylation. The phi (?) and psi (ψ) torsion angles that dictate the conformation of the internal O‐glycosidic linkage in ( II ) are similar to those determined recently in aqueous solution by NMR spectroscopy for unacetylated ( II ) using the statistical program MA′AT, with a greater disparity found for ψ (Δ = ～16°) than for ? (Δ = ～6°).     

(E)‐2‐Methyl‐3‐(2‐methyl‐2‐nitro­vinyl)‐1H‐indole and (E)‐3‐(2‐methyl‐2‐nitro­vinyl)‐2‐phenyl‐1H‐indole

In the title compounds, C₁₂H₁₂N₂O₂, (I), and C₁₇H₁₄N₂O₂, (II), respectively, the indole rings are planar and the vinyl groups lie out of the indole planes, making dihedral angles of 33.48 (5) and 41.31 (8)°, respectively. In (II), the dihedral angle between the phenyl and indole ring planes is 32.06 (6)°. In both mol­ecules, the double bond connecting the methyl­nitro­vinyl group and the indole nucleus adopts an E configuration. Notwithstanding the differences in space group [C2/c for (I) and P2₁2₁2₁ for (II)], the mode of packing of compounds (I) and (II) is determined by similar inter­molecular N—H⋯O hydrogen‐bonding inter­actions, forming chains that run parallel to [101] in (I) and [001] in (II).     

Polymeric Structure and Solid NMR Spectra of Cadmuim ( Ⅱ）Dialkyldithiophosphates(Alkyl=Propyl,Butyl,Isopropyl and Isobutyl)

By dropwise adding thio ligands to concentrated aqueous solutions of Cd(ClO₄)₂·6H₂O, polymeric complexes, Cd(II) O, O'‐dipropyldithiophosphate (1), O, O'‐dibutyl‐dithiophosphate (2), O, O'‐diisopropyl‐dithiophosphate (3) and O, O'‐diisobutyl‐dithiophosphate (4) were obtained. The structure of 4 was determined by X‐ray diffraction analysis, showing that the metal ion sits in distorted tetrahedral sulphur coordination sphere and that the eight‐membered bimetallic rings take the twist chair and boat conformations, alternately. Based on facts that the S(1)—Cd bond length [0.25099(12) nm] is shorter than the other S—Cd bond length [0.25399(12)—0.25701(18) nm] and that the S(1)‐involving angles [113.45(4)°—118.43(5)°] are systematically larger than the normal angles of a tetrahedron, the ligands are hypothesized to be erratically functionalized to Cd(II). To certify the steric nonequivalence of ligands, the compounds were investigated by solid ¹³C, ³¹P and ¹¹³Cd NMR spectroscopy.     

Mixed ab initio QM/MM modeling using frozen orbitals and tests with alanine dipeptide and tetrapeptide

Methodology is discussed for mixed ab initio quantum mechanics/molecular mechanics modeling of systems where the quantum mechanics (QM) and molecular mechanics (MM) regions are within the same molecule. The ab initio QM calculations are at the restricted Hartree–Fock level using the pseudospectral method of the Jaguar program while the MM part is treated with the OPLS force fields implemented in the IMPACT program. The interface between the QM and MM regions, in particular, is elaborated upon, as it is dealt with by “breaking” bonds at the boundaries and using Boys-localized orbitals found from model molecules in place of the bonds. These orbitals are kept frozen during QM calculations. Results from tests of the method to find relative conformational energies and geometries of alanine dipeptides and alanine tetrapeptides are presented along with comparisons to pure QM and pure MM calculations. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 1468–1494, 1999     

Conformational Analysis of Sulfated α-(1→3)-Linked D-Galactobioses Using the Mm3 Force-Field

Abstract

The conformational maps of eight derivatives of the disaccharide α-D-Galp-(1→3)-β-D-Galp sulfated in different positions were obtained using the MM3 force-field specially parameterized for sulfate ester groups. As occurred with MM2, the conformational flexibility of the glycosidic linkage is only slightly hindered by sulfation. A substantial effect of sulfation of the β-D-galactose unit on position 4 shifts the global minimum to positive Ψ_H (C1′-O3-C3-H3) angles, while sulfation at position 2 of the same unit deepens the well at negative Ψ^H angles. On the other hand, sulfation on the α-D-galactose unit has a lesser effect, which in any case tends to stabilize the minimum at negative Ψ_H angles.     

Monte Carlo simulations on short single-stranded oligonucleotides. I. Application to RNA trimers

Monte Carlo (MC) structural simulation of short RNA sequences has been carried out by random variations of the nucleotide conformational angles (i.e., phosphodiester chain torsional angles and sugar pucker pseudorotational angles). All of the chemical bond lengths and valence angles remained fixed during the structural simulation, except those of the sugar pucker ring. In this article we present the simulated structures of RNA trimers—r(AAA) and r(AAG)—obtained at 11°C and 70°C. The influence of various initial conformations (selected as starting points in the MC simulations) on the equilibrium conformations has been discussed. The simulated conformational angles have been compared with those estimated by nuclear magnetic resonance (NMR) spectroscopy. For both of the oligonucleotides studied here, the most stable structures are helical conformations with stacked bases, at 11°C and 70°C. However, when the starting point is a stretched chain, it is found that r(AAA) adopts a reverse-stacked structure at low temperature (11°C), in which the A3 base is located between the A1 and A2 bases. Although the energies of these conformations (helical and reverse stacked) are very close to each other, the potential barrier between them is extremely high (close to 30 kcal/mol). This hinders the conformational transition from one structure to the other at a given temperature (and in the course of a same MC simulation). However, it is possible to simulate this structural transition by heating the reverse-stacked structure up to 500°C and cooling down progressively to 70°C and 11°C: Canonical helical structures have been obtained by this procedure. © 1994 by john Wiley & Sons, Inc.     

A New Method for Molecular Mechanics

A promising new method for optimizing molecular structures is described. In place of the terms involving bond angles and torsion angles, used in the force fields of conventional molecular mechanics, two-body central forces between atoms are used exclusively, resulting in a considerable computational advantage. The program STRFIT, using this method has been tested by comparing geometries obtained with those found using the popular molecular mechanics program MM2 (Allinger) for a variety of cyclic and acyclic molecules. For unstrained molecules, the difference in steric energy between geometries refined by STRFIT and MM2 is only a few tenths of a kilocalorie and up to about a kilocalorie for strained molecules. Geometry optimization with STRFIT, to a structure that is slightly higher in energy than the structure arrived at by MM2 starting from the same initial starting geometry, is three to eight times faster. A complete new package of programs for conveniently and rapidly doing molecular mechanics calculations is described. It includes a convenient algorithm for the input of approximate molecular structures, a rapid structure-optimizing module using a pure Central force-field approach, and a drawing program designed for use with a dot-matrix printer or a laser printer.     

The MM3 force field for amides,polypeptides and proteins

The potential functions for simple amides, several peptides and a small protein have been worked out for the MM3 force field. Structures and energies were fit as previously with MM2, but additionally, we fit the vibrational spectra of the simple amides (average rms error over four compounds, 34 cm^?1), and examined more carefully electrostatic interactions, including charge-charge and charge-dipole interactions. The parameters were obtained and tested by examining four simple amides, five electrostatic model complexes, two dipeptides, six crystalline cyclic peptides, and the protein Crambin. The average root-mean-square deviation from the X-ray structures for the six cyclic peptide crystals was only 0.10 Å for the nonhydrogen atomic positions, and 0.011 Å, 1.0°, and 4.9° for bond lengths, bond angles, and torsional angles, respectively. The parameter set was then further tested by minimizing the high resolution crystal structure of the hydrophobic protein Crambin. The resultant root-mean-square deviations for the non-hydrogen atomic data, in the presence of the crystal lattice, are 0.22 Å, 0.023 Å, 2.0°, and 6.4° for coordinates, bond lengths, bond angles, and torsional angles, respectively.     

Applications of simulated annealing to the conformational analysis of flexible molecules

We describe in this article our solution to the global minimum problem which uses the simulated annealing algorithm of Kirkpatrick. This method is a Metropolis (e-ΔE/kT) Monte Carlo sampling of conformation space with simultaneous constraint of the search by lowering the temperature T so that the search converges on the global minimum. The Anneal-Conformer program has been extensively tested with peptides and organic molecules using either the Amber or MM2 force fields. A history file of the simulated annealing process allows reconstruction of the random walk in conformation space for subsequent examination. Thus plots of distance and dihedral angle changes during the search for the global minimum can be examined to deduce molecular shape and flexibility. A separate program Conf-Gen reads the history file and extracts all low energy conformations visited during the run.     

Ab initio and density functional study of the conformational space of 1C4 α-L-fucose

The conformational space of ¹C₄ α-L-fucose was searched by the MM2^*-SUMM molecular mechanics conformational search technique. The molecular geometries of the first 17 structures of lowest energy were analyzed at the HF/3-21G, 6-31G(d), and generalized gradient approximation (GGA) DFT levels of theory. © 1997 by John Wiley & Sons, Inc.     

4,5-Dihydro-7,8-dimethoxy-1-phenyl-3H-2,3-benzodiazepin-4-one

The title compound, C₁₇H₁₆N₂O₃, is an antagonist for AMPA/kainate receptors. The mol­ecule has its seven-membered oxa­diazo­le ring in a boat conformation. Asymmetry of the two methoxy bond angles is evident, with (Me)O—C—C angles of 115.45 (12) and 124.78 (13)°, and 114.67 (12) and 125.31 (12)°. A centrosymmetric dimer involving the HN—CO moieties, with an N⃛O distance of 2.876 (2) Å, graph set R(8), is further linked into chains through methoxy Csp³—H⃛N hydrogen bonds, with a C⃛N distance of 3.418 (2) Å.     

Conformational analysis and flexibility of carbohydrates using the CICADA approach with MM3

The potential energy hypersurfaces (PES) of several carbohydrate molecules were studied with a new algorithm for conformational searches, CICADA (Channels in Conformational Space Analyzed by Driver Approach) interfaced with the molecular mechanics program MM3(92). The method requires (1) one or a few low-energy conformations as starting points; and (2) designation of the torsion angles important for understanding the conformational behavior of the molecule. The PES is explored by driving separately each selected torsion angle (in both directions) with a concomitant full-geometry optimization at each increment (except for the driven angle). When a minimum has been detected, the molecule is freely optimized, and the minima so detected are then stored if not encountered previously. The new minima serve as starting structures for further explorations. The results from CICADA permit prediction of relative and absolute flexibility and conformational softness for both the entire molecule as well as for individual group rotations and local minima. The carbohydrates analyzed were Me-α-D -glucopyranoside, β-D -GlcNAc(1-2)α-D -Man, and α-D -GalNAc(1-3)[α-L -Fuc(1-2)]Gal-O-Me. All the low-energy conformers along with the transition states and flexibilities features were characterized. CICADA found all minima and low-energy conversion pathways for the disaccharide that were found by a traditional grid search. In contrast to the grid search method, CICADA concentrates mostly on the exploration of the low-energy regions of the PES, thereby saving a significant amount of computational time. The performance of the method opens new routes for exploring conformational space of larger molecules, such as oligosaccharides. © 1995 by John Wiley & Sons, Inc.     

Two modifications of a five‐coordinate silicon complex

TBPY‐5‐34‐(Butane‐1,4‐diyl)(2‐{[1‐(2‐oxidophenyl)ethylidene‐κO]amino‐κN}ethanolato‐κO)silicon, C₁₄H₁₉NO₂Si, crystallizes in two modifications. The monoclinic form, (IIm), was obtained by crystallization over a period of 2 d at room temperature; the orthorhombic form, (IIo), crystallized overnight at 248 K. The main difference between the two molecular structures involves the angles in the equatorial plane of the trigonal bipyramid around silicon. Form (IIm) has an O—Si—O angle of ca 121° and O—Si—C angles of ca 121 and 116°. In form (IIo), the corresponding angles are ∼123, 124 and 111°. There are also significant differences in the packing: (IIm) shows π stacking, whereas (IIo) does not.     

Solid‐state CP/MAS 13C NMR studies on conformational polymorphism in sertraline hydrochloride,an antidepressant drug

The C(2) isotropic chemical shift values in solid‐state CP/MAS ¹³C NMR spectra of conformational polymorphs Form I (δ 28.5) and III (δ 22.9) of (1S,4S)‐sertraline HCl ( 1 ) were correlated with a γ‐gauche effect resulting from the respective 162.6° antiperiplanar and 68.8° (+)‐synclinal C(2)? C(1)? N? CH₃ torsion angles as measured by X‐ray crystallography. The similarity of the solution‐state C(2) chemical shifts in CD₂Cl₂ (δ 22.8) and DMSO‐d₆ (δ 23.4) with that for Form III (and other polymorphs having C(2)? C(1)? N? CH₃ (+)‐synclinal angles) strongly suggests that a conformational bias about the C(1)? N bond exists for 1 in both solvents. This conclusion is supported by density functional theory B3LYP/6‐31G(d)‐calculated relative energies of C(1)? N rotameric models: (kcal) 0.00 [73.8 °C(2)? C(1)? N? CH₃ torsion angle], 0.88 (168.7°), and 2.40 (?63.4°). A Boltzmann distribution of these conformations at 25 °C is estimated to be respectively (%) 80.3, 18.3, and 1.4. Copyright © 2002 John Wiley & Sons, Ltd.