Relative Conformational Energies Research Articles

Ab Initio Study of Conformational Properties of (Z,E,Z)-Cyclonona-1,3,5-Triene

Ab initio HF/6-31G* and MP2/6-31G*//HF/6-31G* methods were used to calculate the relative energies of the important energy-minimum conformations and transition-state geometries of ( Z,E,Z)-cyclonona-1,3,5-triene; the calculated energy barrier for ring inversion of the twist–chair (C1) conformation is 29.35 kJ/mol, while the barrier for swivelling of the trans double bond through the polymethylene bridge is 59.76 kJ/mol.

Conformations of silicon-containing rings. Part 3. Relative conformational energies of alkylated 1,3,5-trisilacyclohexanes as calculated from quantum chemical and molecular mechanics methods

The relative energies of the basic conformations for five series of Si-alkylated derivatives of 1,3,5-trisilacyclohexane 1 with methyl, ethyl, i-propyl and t-butyl alkyl groups have been calculated using quantum chemical (QC) methods (HF and RI-DFT) and the MM3 force field. The results were compared to those from previous NMR investigations. It was found that the QC methods predict for all 1-mono-, cis-1,3-di and cis–cis-1,3,5-tri-alkylated 1 the chair(eq) to be the lowest energy conformation. The QC methods also predict a preference for twisted conformation in the cases of trans-1,3-di- and cis–trans-1,3,5-tri- t-butylated 1. The QC results confirm earlier predictions from the NMR data. In contrast, MM3 fails to calculate relative conformational energies properly. The reason for its failure is discussed.

Conformations of allylic fluorides and stereoselectivities of their diels-alder cycloadditions.

The preparations of new allylic fluorides from the corresponding alcohols are reported. Conformational analysis is achieved by comparison of experimental NMR measurements with theoretical (B3LYP) calculations of relative energies of conformers and J(H,H) and J(H,F) coupling constants. The Diels-Alder reactions of allylic fluorides are investigated experimentally and theoretically. The stereoselectivities of the reactions were determined by NMR analysis and, in one case, by X-ray crystallography. Theoretical predictions of stereoselectivity based upon transition state modeling provided good agreement with experiment. Theoretical models for allylic fluorides and transition state conformations are reported.

ANALYSIS OF THE CONFORMATIONAL COMPOSITION OF 2-ALKYL-4-PHENYL- 1,3,2-OXAZABORINANES

The empirical MM2 and semiempirical AM1 methods were used to calculate the energy of model 2-methyl-4-phenyl-1,3,2-oxazaborinane with full optimization of the molecular geometry. Comparison of the experimental coupling constants for the 2-isobutyl analog and calculated coupling constants as well as the data for the relative energy of the individual conformers indicated that these compounds form a multicomponent equilibrium system containing sofa and a family of half-chair forms.

35Cl NQR Spectra and ab initio Calculations of gem-Substituted 1-Chlorocyclohexane Derivatives

The 35Cl NQR spectra of gem-substiutted 1-chlorocyclohexane derivatives C6H10XCl (X = H, CH3, CH3O, Cl) at 77 K were measured. Ab initio RHF/6-31G(d) calculations of their conformers, and also of conformers of monosubstituted cyclohexanes were performed. Based on the calculation results, the NQR lines were assigned and the conformational energies of the substituents were evaluated. The relative conformational energies of the Cl atom and CH3O group disagree with previous data.

Calculated conformer energies for organic molecules with multiple polar functionalities are method dependent: Taxol (case study)

BackgroundMolecular mechanics (MM) and quantum chemical (QM) calculations are widely applied and powerful tools for the stereochemical and conformational investigations of molecules. The same methods have been extensively used to probe the conformational profile of Taxol (Figure 1) both in solution and at the β-tubulin protein binding site.ResultsIn the present work, the relative energies of seven conformations of Taxol derived from NMR and X-ray analyses were compared with a set of widely used force fields and semiempirical MO methods coupled to a continuum solvent treatment. The procedures not only diverge significantly in their assessment of relative conformational energies, but none of them provide satisfactory agreement with experiment.ConclusionsFor Taxol, molecular mechanics and semiempirical QM methods are unable to provide a consistent energetic ranking of side-chain conformations. For similar highly polar organic structures, "energy-free" conformational search methods are advised.

Computational studies on carbohydrates: I. Density functional ab initio geometry optimization on maltose conformations

Ab initio geometry optimization was carried out on 10 selected conformations of maltose and two 2-methoxytetrahydropyran conformations using the density functional denoted B3LYP combined with two basis sets. The 6-31G* and 6-311++G** basis sets make up the B3LYP/6-31G* and B3LYP/6-311++G** procedures. Internal coordinates were fully relaxed, and structures were gradient optimized at both levels of theory. Ten conformations were studied at the B3LYP/6-31G* level, and five of these were continued with full gradient optimization at the B3LYP/6-311++G** level of theory. The details of the ab initio optimized geometries are presented here, with particular attention given to the positions of the atoms around the anomeric center and the effect of the particular anomer and hydrogen bonding pattern on the maltose ring structures and relative conformational energies. The size and complexity of the hydrogen-bonding network prevented a rigorous search of conformational space by ab initio calculations. However, using empirical force fields, low-energy conformers of maltose were found that were subsequently gradient optimized at the two ab initio levels of theory. Three classes of conformations were studied, as defined by the clockwise or counterclockwise direction of the hydroxyl groups, or a flipped conformer in which the ψ-dihedral is rotated by ∼180°. Different combinations of ω side-chain rotations gave energy differences of more than 6 kcal/mol above the lowest energy structure found. The lowest energy structures bear remarkably close resemblance to the neutron and X-ray diffraction crystal structures. © 2000 John Wiley & Sons, Inc.* J Comput Chem 21: 1204–1219, 2000

Conformational equilibrium and potential energy surface of 1-fluorobutane by microwave spectroscopy and Ab initio calculations

The rotational spectra of four (GT, TT, TG, and GG) of the five possible conformers of 1-fluorobutane have been assigned by combining free jet and conventional microwave spectroscopy. The geometry optimization was performed at the MP2 (full) level of theory with the 6-31G (d) and 6-311G (d, p) basis sets and by using the B3LYP (3df, 3pd) density functional method. The relative stability of the five rotamers is calculated at the QCISD (T)/6-311G (d, p) level of theory. In spite of the fact that ab initio calculations indicated the unobserved GG' conformer to be more stable than at least one of the observed conformers it was not possible to detect its rotational spectrum. GT and TG are the most and the least stable species, respectively. The rotational spectra of several vibrational satellites of the four conformers have been studied by conventional microwave spectroscopy. The overall conformational equilibrium is governed by the two-dimensional potential energy surface of the skeletal torsions MeC-CC and FC-CC, which have been evaluated by a flexible model analysis, based on the experimental values of the relative conformational and vibrational energy spacings, and on the shifts of second moments of inertia upon conformational change and vibrational excitation. The relative energy of the fifth stable conformer (GG') was determined to be 333 cm(-1) from flexible model calculations, and to be 271 cm(-1) from the most accurate ab initio calculations.

Conformational Equilibria of Peroxynitrous Acid in Water: A First-Principles Molecular Dynamics Study

An aqueous solution of peroxynitrous acid has been studied using first-principles molecular dynamics simulations based on density functional theory. The relative Helmholtz energies of different conformers have been determined via thermodynamic integration with constraints. At contrast to the gas phase, only two conformers, a cis and a trans isomer, are present in solution and their relative Helmholtz energy is enhanced with respect to the gas phase. The average structural properties of the two conformational forms on the other hand are very close to the respective gas phase values. The interconversion pathway between the two conformers has been determined, and the Helmholtz energy profile for the isomerization reaction in solution is presented. The rotational barrier is calculated to be substantially higher than in gas phase due to a strong rearrangement of the solvent during the reaction. The structure of the transition state can only be described correctly when the solvent is taken explicitly into account. Our calculations indicate that the cis form is the dominant species in aqueous solution at ambient temperatures.

Cyclopentapeptides as Flexible Conformational Templates

Studies of 3D models for cyclopentapeptides (CPP's) employing only NMR spectroscopy encounter a serious problem. Because of conformer averaging, 3D structure(s) derived directly from NMR data may not correspond to the energy minimum (minima) with low relative conformational energy. At the same time, independent energy calculations can determine all low-energy conformers for the CPP backbone. The two approaches are compared in this study by results obtained for cyclo(d-Pro1-Ala2-Ala3-Ala4-Ala5). Contrary to the conclusion (predominance of the βII‘γ type conformer) of earlier NMR studies, independent energy calculations found a different family of low-energy 3D structures that are consistent both with the NMR data in DMSO and with the known X-ray data on CPP's. The preferable Ala4 conformations were found in the αR/αL regions suggesting studies of cyclo(d-Pro1-Ala2-Ala3-Aib4-Ala5) which was synthesized. Further NMR studies confirmed the results of the independent energy calculations. The independent energy calculations have been applied also to cyclo(Arg1-Gly2-Asp3-d-Phe4-Val5) and cyclo(Arg1-Gly2-Asp3-Phe4-d-Val5). Both peptides are almost equally potent inhibitors of binding of αIIbβ3 integrins to fibrinogen and of αVβ3 integrins to vitronectin. If both of them possess a NMR-predicted conformer of the βII‘γ type, however, the conformations of the active sequence, Arg1-Gly2-Asp3, should be dissimilar in these two peptides. This discrepancy is eliminated in the 3D pharmacophore model proposed by independent energy calculations. The model is also in good agreement with the model by other authors that was confirmed by X-ray studies.

Peptide models XXVII. An exploratory ab initio study on the 21st amino acid side-chain conformations of N-formyl-L-selenocysteinamide (For-L-Sec-NH2) and N-acetyl-L-selenocysteine-N-methylamide (Ac-L-Sec-NHMe) in their γL backbone conformation

Selenocysteine is expected to have 9 × 9 = 81 conformations [3 × 3 = 9 backbone: ψ (g+,a,g-) × ϕ (g+,a,g-) and 3 × 3 = 9 side-chain: χ1 (g+,a,g-) × χ2 (g+,a,g-)]. In the present study, all the torsional modes of the side-chain (χ1: rotation about the Cα-Cβ and χ2: rotation about the Cβ-Se bonds) were investigated in the relaxed γL backbone [(ϕ,ψ); (g-,g+)] conformation. Seven out of the nine expected minima were found at the RHF/3-21G level of theory for N-formyl-L-selenocysteinamide (For-L-Sec-NH2) and N-acetyl-L-selenocysteine-N-methylamide (Ac-L-Sec-NHMe). The stabilization energy exerted by the -CH2-SeH side-chain has been compared with that of -CH2-SH and -CH2-OH. Relative energies of the various conformers were also obtained via single point calculations at the B3LYP/6-31G(d,p) level of theory. Topological analysis of the electron density has been performed by Bader's Atoms in Molecule (AIM) approach using the results. The structures were also optimized at the B3LYP/6-31+G(d,p) level of theory.Key words: selenocysteine side-chain conformations, ab initio MO study, Multidimensional Conformational Analysis (MDCA), Atoms in Molecules (AIM), Bader's electron density analysis.

Computational studies on carbohydrates: I. Density functionalab initio geometry optimization on maltose conformations

Ab initio geometry optimization was carried out on 10 selected conformations of maltose and two 2-methoxytetrahydropyran conformations using the density functional denoted B3LYP combined with two basis sets. The 6-31G and 6-311CCG basis sets make up the B3LYP/6-31G and B3LYP/6-311CCG procedures. Internal coordinates were fully relaxed, and structures were gradient optimized at both levels of theory. Ten conformations were studied at the B3LYP/6-31G level, and five of these were continued with full gradient optimization at the B3LYP/6-311CCG level of theory. The details of the ab initio optimized geometries are presented here, with particular attention given to the positions of the atoms around the anomeric center and the effect of the particular anomer and hydrogen bonding pattern on the maltose ring structures and relative conformational energies. The size and complexity of the hydrogen-bonding network prevented a rigorous search of conformational space by ab initio calculations. However, using empirical force fields, low-energy conformers of maltose were found that were subsequently gradient optimized at the two ab initio levels of theory. Three classes of conformations were studied, as defined by the clockwise or counterclockwise direction of the hydroxyl groups, or a flipped conformer in which the -dihedral is rotated by180 .D ifferent combinations of! side-chain rotations gave energy differences of more than 6 kcal/mol above the lowest energy structure found. The lowest energy structures bear remarkably close resemblance to the neutron and X-ray diffraction crystal structures. c 2000 John Wiley & Sons, Inc. JC omput Chem 21: 1204-1219, 2000

Conformers and intramolecular hydrogen bonding of the oxalic acid monomer and its anions

Density functional theory, B3LYP/6-31G** and B3LYP/6-311+G(2d,p), and ab initio MP2/6-31G** calculations have been carried out to investigate the conformers, transition states, and energy barriers of the conformational processes of oxalic acid and its anions. QCISD/6-31G** geometrical optimization is also performed in the stable forms. Its calculated energy differences between the two most stable conformers are very near to the related observed value at 7.0 kJ/mol. It is found that the structures and relative energies of oxalic acid conformers predicted by these methods show similar results, and that the conformer L1 (C2h) with the double-interfunctional-groups hydrogen bonds is the most stable conformer. The magnitude of hydrogen bond energies depends on the energy differences of various optimized structures. The hydrogen bond energies will be about 32 kJ/mol for interfunctional groups, 17 kJ/mol for weak interfunctional groups, 24 kJ/mol for intra-COOH in (COOH)2, and 60 kJ/mol for interfunctional groups in (COOH)COO−1 ion if calculated using the B3LYP/6-311+G(2d,p) method. © 2000 John Wiley & Sons, Inc. Int J Quant Chem 76: 541–551, 2000

An ab initio molecular orbital study of the conformational energies of 3-alkyltetrahydro-2 H-thiopyrans (tetrahydrothiopyrans, thiacyclohexanes, thianes)

Ab initio 6-31G ∗ and 6-31G ∗∗ basis sets and density functional theory (pBP/DN ∗∗) were used to calculate the geometry of the chair conformer of tetrahydro-2 H-thiopyran (tetrahydrothiopyran, thiacyclohexane, thiane). 6-31G ∗ geometry optimization and MP2/6-31G ∗//6-31G ∗ single point energy methods were used to calculate the relative energies and conformational energies (−Δ G° or A values, kcal/mol) of 3-alkyltetrahydro-2 H-thiopyrans (Me=1.56; Et=1.22; i-Pr=0.91; t-Bu=4.54; neo-Pent=1.06; SiMe 3=2.01). The MP2/6-31G ∗//6-31G ∗ calculated conformational energies of the 3-alkylthiacyclohexanes are generally smaller than those for the corresponding alkylcyclohexanes and 4-alkylthiacyclohexanes, but are similar to those calculated for 2-alkylthiacyclohexanes. Plots of the calculated conformational energies of the 3-alkylthiacyclohexanes versus the calculated −Δ G° of the corresponding alkylcyclohexanes (slope=0.901 and r=0.997 for 6-31G ∗ and slope=0.845 and r=0.994 for MP2/6-31G ∗//6-31G ∗), 2-alkylthiacyclohexanes (slope=1.273 and r=0.981 for 6-31G ∗ and slope=1.273 and r=0.986 for MP2/6-31G ∗//6-31G ∗), and 4-alkylthiacyclohexanes (slope=0.888 and r=0.997 for 6-31G ∗ and slope=0.839 and r=0.994 for MP2/6-31G ∗//6-31G ∗) are linear. Both carbon–sulfur bond lengths in the 3-alkylthiacyclohexanes are generally in the narrow range of 1.815 and 1.818 Å and the C(2)–H ax and C(6)–H ax bond lengths are slightly longer than the respective C(2)–H eq and C(6)–H eq bond lengths. The C–S–C bond angles vary from 97.1 to 99.0° and the C(2)–C(3)–C(7) and C(4)–C(3)–C(7) bond angles in the most stable axial conformer are larger that the corresponding angles in its most stable equatorial conformer.

Theoretical study of cis-hydroxyl acrylic acid (cis-CH(OH)[dbnd]CH(COOH)): intramolecular hydrogen bonding and conformers

Ab initio MP2/6-31G∗∗ and density functional theory B3LYP/6-31G∗∗ and B3LYP/6-311+G(2d,p) calculations have been carried out to investigate the structures and the intramolecular hydrogen bonding of cis-hydroxyl acrylic acid. It evidences that various types of intramolecular hydrogen bonding influence the conformers and eight conformers appear in this study. By applying the first two levels, we find that seven conformers are planar with CS symmetry except conformer L7, but by B3LYP/6-311+G(2d,p) level, L7 and L6 conformers become non-planar. The structures and relative energies of cis-hydroxyl acrylic acid conformers predicted by these levels show similar results, and it is found that the double intramolecular hydrogen bonding L1 conformer is the most stable among them. The same three levels of calculation were also employed to the transition states and the energy barriers. Three types of intramolecular hydrogen bonding were found in different conformers. The magnitude of computed values from the “localized hydrogen bonding analysis method” is about 80kJ/mol for interfunctional groups hydrogen bonding, about 30∽40kJ/mol for weak interfunctional groups hydrogen bonding and about 13kJ/mol for intra-COOH hydrogen bonding. The stability and the planar structure of this molecule closely depend on the intramolecular hydrogen bonding.

Mixedab 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

Analysis of the conformational composition of the 4,5- and 5,6-dimethyl-1,3,2-oxazaborinane stereoisomers

An energy for the molecules of cis and trans 4,5- and 5,6-dimethyl-1,3,2-oxazaborinanes, and of model 1,3,2-oxazaborinanes and tetrahydro-1,3-oxazines with full geometric optimization has been calculated using empirical (MM2) and semiempirical (AM1) methods. From a comparison of experimental and calculated coupling constants and the relative energies of individual conformers it follows that molecules of the cyclic boron esters form a multicomponent equilibrium system, comprizing sofa and half-chair forms with an equatorial orientation of the N−H bond.

Theoretical studies of the first strongly allowed singlet states of 3-desoxy analogs of previtamin D, vitamin D, and their E-isomers

The characteristics of the first singlet excited states (oscillator strength, Franck-Condon and 0–0 transitions) of isomeric seco-steroids, 3-desoxy-analogs of vitamin D ( 6), previtamin D ( 8), and their 5E-isomers ( 7, 9), have been calculated using the semiempirical QCFF method. The results obtained have been compared with the available experimental observations, as well as ground state ab initio calculations at the HF/6-31G level and agree well for vitamin D and its 5E-isomer. Comparison of UV absorption characteristics of previtamin D with calculations of 3-desoxy-previtamin D conformers indicates the need for detailed modeling of the bandshape to attain good correlation with experiment. The failure of the semiempirical approach in the case of pre-vitamin D is also reflected in the poor agreement with ab initio results for the relative ground state conformer energies. This problem can be attributed to the importance of CH/π interactions in the system which are followed via Mulliken population analysis. Using a Boltzmann conformational distribution based on the ab initio relative energies of 3-desoxy-previtamin D conformers in combination with QCFF/sol results on the absorption characteristics leads to good agreement with experiment.

Structure and Conformational Equilibrium in Substituted [(η4-butadiene)Fe(CO)3] Complexes: A Density Functional Study

A very good correlation was observed between the relative energies of the stable conformers in substituted derivatives of [(η4-butadiene)Fe(CO)3], obtained from density functional calculations performed on the conformational equilibria that correspond to C−C rotations (see diagram), and the experimentally observed diastereomeric ratios in several kinds of reactions.

Fluctuating Charge, Polarizable Dipole, and Combined Models: Parameterization from ab Initio Quantum Chemistry

We performed studies of fluctuating charge, fluctuating dipole, and combined models for substituted benzenes and concluded that dipoles are necessary to avoid errors in important cases. Force fields incorporating fluctuating dipoles for alanine, serine, and phenylalanine were developed that accurately reproduce both relative conformational energies and cooperative many-body energies as given by ab initio quantum chemical calculations. The polarization model was fit to quantum chemical calculations of changes in the electrostatic potential (ESP) induced by applied perturbations. The electrostatic model was completed by adding fixed charges fit to the zero-field quantum chemical ESP. All intramolecular and Lennard−Jones parameters, and some torsional parameters, were taken from the OPLS-AA force field of Jorgensen and co-workers. Key torsional parameters were refit to quantum chemical structures and energies.