DFT-GIAO study of aryltetralin lignan lactones: conformational analyses and chemical shifts calculations

The conformational properties of polygamain and morelensin, two aryltetralin lignan lactones, have been investigated in both the gas-phase and chloroform solution using DFT calculations at the B3LYP/6-311G(d,p) level. Results indicate that the conformation of polygamain is very rigid. Thus, the conformational flexibility of its five-membered rings is considerably restricted as reflects the pseudorotational parameters of the corresponding envelope conformations. On the other hand, morelensin shows a notable conformational flexibility, which is mainly due to its two methoxy groups. Accordingly, 16 minimum energy conformations with relative energies smaller than 2.4 kcal/mol were detected. Furthermore, chemical shifts for 13C nuclei have been calculated using the GIAO method, results being compared with experimental data. A good agreement was found for both polygamain and morelensin.     

On the multiple-minima problem in the conformational analysis of polypeptides. IV. Application of the electrostatically driven Monte Carlo method to the 20-residue membrane-bound portion of melittin

The conformational space of the membrane-bound portion of melittin has been searched using the electrostatically driven Monte Carlo (EDMC) method with the ECEPP/2 (empirical conformational energy program for peptides) algorithm. The former methodology assumes that a polypeptide or protein molecule is driven toward the native structure by the combined action of electrostatic interactions and stochastic conformational changes associated with thermal movements. The algorithm produces a Monte Carlo search in the conformational hyperspace of the polypeptide using electrostatic predictions and a random sampling technique, combined with local minimization of the energy function, to locate low-energy conformations. As a result of 8 test calculations on the 20-residue membrane-bound portion of melittin, starting from six arbitrary and two completely random conformations, the method was able to locate a very low-energy region of the potential with a well-defined structure for the backbone. In all of the cases under study, the method found a cluster of similar low-energy conformations that agree well with the structure deduced from x-ray diffraction experiments and with one computed earlier by the build-up procedure.     

Study of the conformational profile of the norbornane analogues of phenylalanine.

The conformational profile of the eight stereoisomeric 2-amino-3-phenylnorbornane-2-carboxylic acids (2-amino-3-phenylbicyclo[2.2.1]heptane-2-carboxylic acids) has been assessed by computational methods. These molecules constitute a series of four enantiomeric pairs that can be considered as rigid analogues of either L- or D-phenylalanine. The conformational space of their N-acetyl methylamide derivatives has been explored within the molecular mechanics framework, using the parm94 set of parameters of the AMBER force field. Local minimum energy conformations have been further investigated at the ab initio level by means of the Hartree-Fock and second order Moller-Plesset perturbation energy calculations using a 6-31G(d) basis set. The results of the present work suggest that the bulky norbornane structure induces two kinds of conformational constraints on the residues. On one hand, those of a steric nature directly imposed by the bicycle on the peptide backbone and, on the other hand, those that limit the orientations attainable by the phenyl ring which, in turn, reduces further the flexibility of the peptide backbone. A comparative analysis of the conformational profile of the phenylnorbornane amino acids with that of the norbornane amino acids devoid of the beta-phenyl substituent suggests that the norbornane system hampers the residue to adopt extended conformations in favour of C7-like structures. However, the bicycle itself does not impart a clear preference for any of the two possible C7 minima. It is the aromatic side chain, which is forced to adopt an almost eclipsed orientation, that breaks this symmetry introducing a marked preference for a single region of the (phi, psi) conformational space in each of the phenylalanine norbornane analogues investigated.     

Theoretical conformational analysis of tripeptides. N-acetyl-L-alanyl-L-alanyl-L-alanyl methylamide]

The minimization procedure has been used for calculation of the local minimum conformations of threepeptide--Ac-(L-Ala)3-NHMe without intramolecular H-bonds. The significant energy deviations from additivity found, arising with increase backbone length to three links, can be considered as the evidence for mutual dependence of conformational states of the neighbouring and terminal amino acid residues. It have been shown that stability of alpha-helix form for alanine threepeptide in contrary to corresponding dipeptide is noticeably higher due to stabilizing effect of dispersion interactions. The results of calculations are compared with the data on conformational distrubution of the threepeptide fragments in proteins with known three dimensional structure. The important role of the backbone interaction in protein chain have been marked.     

Comparative conformational analysis of cholesterol and ergosterol by molecular mechanics

A comparative conformational analysis of cholesterol and ergosterol has been carried out using molecular mechanics methods. These studies are aimed at giving a better understanding of the molecular nature of the interaction of these sterols with polyene macrolide antibiotics. Structures of cholesterol and ergosterol determined by X-ray methods have been used as initial geometries of these molecules for force field calculations. The calculation of steric energy has also been made for conformations which do not appear in the crystal. The latter conformers have different conformations of the side chain as well as different conformations of rings A and D. The rotational barriers around bonds C17–C20 and C20–C22 have also been calculated. The results obtained on differences and similarities in the conformations of cholesterol and ergosterol allow us to postulate a mechanism for differential interaction with the antibiotics. The relatively rigid side chain of ergosterol (stretched molecule) in comparison with the flexible side chain of cholesterol (bent molecule), allows better intermolecular contact of the first sterol molecule with a polyene macrolide and in consequence facilitates complex formation involving Van der Waal's forces.     

Modeling the anti-CEA antibody combining site by homology and conformational search.

A model for an antibody specific for the carcinoembryonic antigen (CEA) has been constructed using a method which combines the concept of canonical structures with conformational search. A conformational search technique is introduced which couples random generation of backbone loop conformations to a simulated annealing method for assigning side chain conformations. This technique was used both to verify conformations selected from the set of known canonical structures and to explore conformations available to the H3 loop in CEA ab initio. Canonical structures are not available for H3 due to its variability in length, sequence, and observed conformation in known antibody structures. Analysis of the results of conformational search resulted in three equally probable conformations for H3 loop in CEA. Force field energies, solvation free energies, exposure of charged residues and burial of hydrophobic residues, and packing of hydrophobic residues at the base of the loop were used as selection criteria. The existence of three equally plausible structures may reflect the high degree of flexibility expected for an exposed loop of this length. The nature of the combining site and features which could be important to interaction with antigen are discussed.     

Study of the conformational profile of the cyclohexane analogs of L-phenylalanine.

The conformational profile of the conformationally constrained cyclohexane analogs of phenylalanine (1-amino-2-phenylcyclohexanecarboxylic acids, c6Phe) was assessed using computational methods. For this purpose, the conformational space of the N-acetyl methylamide derivatives of the stereoisomers (2S,3R)c6Phe and (2S,3S)c6Phe was explored by computing their respective Ramachandran maps, and low-energy minima were characterized at molecular mechanics level by means of the AMBER program, using the parm94 force field set of parameters. In order to assess the performance of the molecular mechanics calculations, each of the low-energy conformations was also investigated further at the ab initio level. Accordingly, the molecular mechanics geometries were used as starting conformations to perform full geometry optimizations at the Hartree-Fock level, using a 6-31G(d) basis set. Analysis of the results revealed that the cyclohexane structure directly induces some restrictions on the backbone, and constrains the orientation of the aromatic side-chain to two narrow regions for each stereoisomer. The conformational profile of these amino acids is then explained on the grounds of the interaction between the rigidly held phenyl ring and the main chain NH and CO groups. The results obtained are in good accordance with the experimental observations.     

Molecular conformational analyses of dehydroalanine analogues

The conformational preferences of dehydroalanine (ΔAla) were examined through ab initio calculations. The geometries of the minimum energy conformations for N-formyldehydro alanilamide and N-acetyl-N′-methylamide of dehydroalanine were determined by gradient optimization at the HF/6-31G* level, and correlation corrections were examined with MP2 single-point energy calculations. Furthermore, HF/3-21G ab initio geometry optimizations were performed on nine conformations of the model tripeptide N-acetyl-N′-methylamide of didehydroalanine. The results indicate that the C₅ is the lowest energy conformation at all levels of theory. However, the relative energy of the helix conformation decreases when the number of ΔAla residues in the peptide chain increases. On the other hand, significant variations of the geometry upon conformational change were observed for the three compounds investigated. These results permit to extract important conformationally dependent geometry trends. The results of this study were compared to x-ray diffraction data on single crystals of dehydroalanine-containing peptides. © 1995 John Wiley & Sons, Inc.     

Solution conformational study of Scyliorhinin I analogues with conformational constraints by two-dimensional NMR and theoretical conformational analysis.

Two analogues of Scyliorhinin I (Scyl), a tachykinin with N-MeLeu in position 8 and a 1,5-disubstituted tetrazole ring between positions 7 and 8, introduced in order to generate local conformational constraints, were synthesized using the solid-phase method. Conformational studies in water and DMSO-d6 were performed on these peptides using a combination of the two-dimensional NMR technique and theoretical conformational analysis. The algorithm of conformational search consisted of the following three stages: (i) extensive global conformational analysis in order to find all low-energy conformations; (ii) calculation of the NOE effects and vicinal coupling constants for each of the low energy conformations; (iii) determining the statistical weights of these conformations by means of a nonlinear least-squares procedure, in order to obtain the best fit of the averaged simulated spectrum to the experimental one. In both solvents the three-dimensional structure of the analogues studied can be interpreted only in terms of an ensemble of multiple conformations. For [MeLeu8]Scyl, the C-terminal 6-10 fragment adopts more rigid structure than the N-terminal one. In the case of the analogue with the tetrazole ring in DMSO-d6 the three-dimensional structure is characterized by two dominant conformers with similar geometry of their backbones. They superimpose especially well (RMSD = 0.28 A) in the 6-9 fragments. All conformers calculated in both solvents superimpose in their C-terminal fragments much better than those of the first analogue. The results obtained indicate that the introduction of the tetrazole ring into the Scyl molecule rigidifies its structure significantly more than that of MeLeu.     

A simple hydrogen bond potential function for conformational studies

Since hydrogen bonding plays an important role in determining energetically favourable conformations of biological molecules, a computationally simple and convenient semiempirical function has been evaluated by constraining a function to conform to the experimentally observed data for isolated simple systems of hydrogen bonded dimers. The function is found to be satisfactory for use in conformational energy calculations.     

The conformational analysis of adenosine triphosphate by classical potential energy calculations

The conformational analysis of adenosine triphosphate was conducted by using classical potential energy calculations. All rotatable bonds were examined, i.e., no dihedral angles were fixed at predetermined conformations except for the ribofuranose ring, which was held in the C(3′)-endo conformation—the conformation observed for adenosine in the crystal state. The energy terms included in the total energy expression consist of nonbonded pairwise interaction, electrostatic pairwise interaction, free energy of solvation, and torsional bond potentials. Two separate approaches were used in the conformational analyses. The first consisted of a sequential fragment approach were four bonds were rotated simultaneously at 30° increments. Each fragment overlapped the preceding one by at least one bond. All rotors were then simultaneously examined at their minima and at ±15°. The second approach consisted of a coarse grid search where all rotors were examined simultaneously, but only at staggered positions. The low-energy conformations thus obtained were then used as starting conformations for a minimization routine based on the method of conjugate directions. The first approach required about 40 hr of central processing unit (CPU) computer time, while the coarse grid/minimization approach required about 4 hr of CPU time. Both the sequential fragment approach and the minimization approach yielded lowest-energy conformations which are remarkably similar to the solid-state conformation of C(3′)-endo ATP.     

Computational analysis of two similar neuropeptides yields distinct conformational ensembles

Conformational states and thermodynamic properties for two similar neuropeptides, GDPFLRF-NH(2) and GYPFLRF-NH(2), have been computed by Monte Carlo simulated annealing (MCSA) conformational searches and Metropolis Monte Carlo (MMC) calculations. These peptides were recently shown to have dramatically different conformations in solution by NMR [Edison et al., J Neuroscience 1999;19:6318-6326]. Final conformations of multiple independent MCSA runs were the starting points for MMC calculations, and conformations saved at intervals during MMC runs were characterized in terms of total energy, configuration entropy, side-chain fraction population, and ensemble average inter-nuclear distances. Without the use of any NMR data-generated pseudo-potentials, the present calculations were in excellent qualitative agreement with all previous NMR experimental data and provided a foundation by which to more quantitatively interpret the experimental NMR results. Proteins 2000;40:367-377.     

Differences in conformational behavior of ATA and TAT sequences in single strand DNA trimer.

The conformational behavior of single strand (ss) TAT and ATA trimers of DNA have been studied by computational chemistry tools including CICADA software interfaced with AMBER molecular mechanics and dynamics. The Single-Coordinate-Driving (SCD) method has been used in conjunction with molecular dynamics simulated annealing. It has been revealed that the conformational flexibility of each sequence differs substantially from the other one. Four common conformational families have been found for both trimers. These are: helical, reverse-stacked (base 3), half-stacked (base 3), reverse-stacked (base 1). However, the energies of conformers representing the families are different for both the studied systems. An additional conformational family, bulged, has been found for ss(ATA), while ss(TAT) has been found also in half-stacked (base 1) conformation. In general, ss(TAT) exhibits a higher number of low energy conformations while ss(ATA) shows one interesting low energy conformational interconversion between reverse-stacked (A3) family and half-stacked (A3) family. The high conformational variability of the trimers has been confirmed by flexibility analysis and by molecular dynamics simulations, which have also shown the conformational stability of single conformational families. It has been concluded that the methodology used is able to provide a very detailed picture of the conformational space of these molecules.     

Model for the conformational analysis of hydrated peptides. Effect of hydration on the conformational stability of the terminally blocked residues of the 20 naturally occurring amino acids

The effects of hydration are included in empirical conformational energy computations on oligopeptides by means of a modified hydration-shell model. Free energy terms are introduced to account for “specific hydration” due to water–solute hydrogen bonding and for “nonspecific hydration” describing the interaction of the solute with water molecules in a first-neighbor shell. The dielectric constant has been doubled (over the value used for calculations in the absence of water) to take into account the presence of solvent. Computations were carried out for the N-acetyl-N′-methylamides of the 20 naturally occurring amino acids. Conformational energy maps are compared with similar maps calculated in the absence of hydration. Minimum-energy conformations are located and compared with the corresponding minima for unhydrated peptides in terms of ordering with respect to potential energy, the dihedral angles at the minima, and the presence of intramolecular hydrogen bonds. The Boltzmann factors for various conformational regions are altered significantly on hydration in some cases. These changes can be explained in terms of differences in the hydration free energy terms for various conformations.     

Computational conformational analysis of cyclohexaglycyl

Conformational hyperspace searching procedures have been used in conjunction with molecular mechanics calculations to characterize a series of minimum energy cyclohexaglycyl conformations (MECs). The key MECs are identical to those found by Scheraga m an earlier study using different computational techniques. The gas phase global MEC is stabilized by numerous intramolecular hydrogen bonds between (solvent) inaccessible amide groups; in contrast to the solution and crystalline phase global MEC where all of the amide groups are accessible for solvent interactions and/or intermolecular hydrogen bonding. The conformational hyperspace searching procedures are also extremely useful in protein model building studies.     

Theoretical conformational analysis of doulble-stranded polynucleotides]

Calculations of intramolecular interaction energy of two-stranded helical homopolynucleotide in the function of nine conformational variables have been carried out by the method of atom-atom potential functions. Four of these variables determine mutual position of base pairs, other four--deoxiribose ring conformation and other one--orientation of this ring with respect to the base. For this purpose an algorythm connecting dependent variables with independent ones has been developed. The investigation of energy function has shown that in the space of conformational parameters there are two valleys, which correspond to A-and B-families of conformations. Experimentaly determined conformations of two-stranded helical polynucleotides are located along the bottoms of these valleys. Along the bottom of each valley the intramolecular interaction energy changes rather little when conformational parameters change within a wide range. The valleys are separated by an energetical barrier.     

Mean geometry of the thiopeptide unit and conformational features of dithiopeptides and polythiopeptides

The mean geometry of the thiopeptide [Ca-N-C(=S)-Ca] unit has been derived from an analysis of X-ray crystal structure data, as well as MM2 and Gaussian 80/82 calculations. The conformational flexibilities of dithiopeptides with glycl- and alanyl-side chains have been investigated by molecular mechanics. Minimum energy conformations were examined using interactive computer graphics molecular modeling techniques. Alanyl-dithiopeptide substitution within an oligopeptide results in considerable restriction of conformational freedom whereas the effect is minimal for glycyl-dithiopeptide substitution. Polyglycyl-thiopeptide adopts a left-handed three or fourfold or right-handed threefold helical structure with favorable interchain C = S...H-N hydrogen bond interactions. A poly-L-alanyl-thiopeptide prefers a left-handed threefold poly-L-proline-like helical structure.     

CNDO/2 quantum-mechanical calculations of the conformational flexibility of the diketopiperazine skeleton

Eight conformers typical of diketopiperazine (DKP) ring folding were chosen for analysis. Conformational energy calculations were carried out using the semiempirical quantummechanical CNDO/2 method. The results obtained confirm considerable flexibility of the DKP skeleton. As the degree of folding increases, twisted boat conformations with the nonplanar peptide bonds tend to be more stable, while more rigid regular boat conformations with planar peptide bonds appear to be less stable than a flat one. The CNDO/2 method was found to be reliable enough for conformational studies of cyclic peptide skeletons with cis-peptide bonds.