Computational study of the conformational preferences of the (R)-8-amino-pentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane-8-carboxylic acid monopeptide.

alpha-Amino acids are important building blocks for the synthesis of a large number of bioactive compounds and pharmaceutical drugs. However, a literature survey revealed that no theoretical conformational study of alpha-amino acids with cage carbon frameworks has been performed to date. This paper reports the results of a conformational study on the (R)-8-amino-pentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane-8-carboxylic acid monopeptide (cage monopeptide), using molecular mechanics and ab initio methods. The in vacuo Ramachandran maps computed using the different parameterizations of the AMBER force field show the C7eq structure as the most favourable conformation, in contrast to the C7ax structure, that is the lowest energy conformation at the ab initio level. Analysis of these maps reveals the helical preference for the monopeptide and provides the potential for the cage residue to be incorporated into constrained peptide analogues.     

Electron Correlated Ab Initio Study of Amino Group Flexibility for Improvement of Molecular Mechanics Simulations on Nucleic Acid Conformations and Interactions

High level ab initio studies demonstrate substantial conformational flexibility of amino groups of nucleic acid bases. This flexibility is important for biological functions of DNA. Existing force field models of molecular mechanics do not describe this phenomenon due to a lack of quantitative experimental data necessary for an adjustment of empirical parameters. We have performed extensive calculations of nucleic acid bases at the MP2/6-31G(d,p) level of ab initio theory for broad set of amino group configurations. Two-dimensional maps of energy and geometrical characteristics as functions of two amino hydrogen torsions have been constructed. We approximate the maps by polynomial expressions, which can be used in molecular mechanics calculations. Detailed considerations of these maps enable us to propose a method for determination of numerical coefficients in the developed formulae using restricted sets of points obtained via higher-level calculations.     

Structural features of linear (alphaMe)Val-based peptides in solution by photophysical and theoretical conformational studies

In continuation of our studies on the determination of the structural features of functionalized peptides in solution by combining time-resolved fluorescence data and molecular mechanics results, the conformational features of a series of linear, L-(alphaMe)Val-based peptides have been investigated in methanol. These foldamers have the general formula F[(alphaMe)Val](r)-T-[(alphaMe)Val](2)NHtBu, where (alphaMe)Val = C(alpha)-methylvaline and r = 0-3, while F [= fluoren-9-ylmethoxycarbonyl (Fmoc)] and T [= 2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-carboxylic (Toac)] are a fluorophoric N(alpha)-protecting group and a nitroxide-based alpha-amino acid quencher, respectively. According to ir and CD spectra, the longest term of the series (r = 3) attains a 3(10)-helical structure, while the other peptides populate an intramolecularly H-bonded, 3(10)-helix-like conformation affected by dynamic helical distortions, which are enhanced by the shortness of the backbone chain. Such distortions are reflected in both the energy of the stretching mode and the molar extinction coefficient of the H-bonded N-H groups, the former being higher and the latter smaller than those of a stable 3(10)-helix. Steady-state and time-resolved fluorescence measurements in methanol show a strong quenching of Fmoc by the Toac residue, located at different helix positions, depending on the r value. Comparison of quenching efficiencies and lifetime preexponents with those theoretically obtained from the deepest energy minimum conformers, assuming a F?rster mechanism, is satisfactory. The computed structures exhibit a rather compact arrangement, which accounts for the few sterically favored conformations for each peptide, in full agreement with the time-resolved fluorescence data. Orientational effects between the probes must be taken into account for a correct interpretation of the fluorescence decay results, implying that interconversion among conformational substates involving the probes is slower than the energy transfer rate.     

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.     

Molecular dynamics study of the conformations of glycosidic linkages in sialic acid modified ganglioside GM3 analogues

The objective of the present study is to model the analogues of monosialoganglioside (GM3) by making modifications in its sialic acid residue with different substitutions in aqueous environment and to determine their structural stability based upon computational molecular dynamics. Molecular mechanics and molecular dynamics investigation was carried out to study the conformational preferences of the analogues of GM3. Dynamic simulations were carried out on the analogues of GM3 varying in the substituents at C-1, C-4, C-5, C-8 and C-9 positions of their sialic acid or Neuraminic acid (NeuAc) residue. The analogues are soaked in a periodic box of TIP3P water as solvent and subjected to a 10 ns molecular dynamics (MD) simulation using AMBER ff03 and gaff force fields with 30 ps equilibration. The analogue of GM3 with 9-N-succNeuAc (analogue5, C9 substitution) was observed to have the lowest energy of ?6112.5 kcal/mol. Graphical analysis made on the MD trajectory reveals the direct and water mediated hydrogen bonds existing in these sialic acid analogues. The preferable conformations for glycosidic linkages of GM3 analogues found in different minimum energy regions in the conformational maps were identified. This study sheds light on the conformational preferences of GM3 analogues which may be essential for the design of GM3 analogues as inhibitors for different ganglioside specific pathogenic proteins such as bacterial toxins, influenza toxins and neuraminidases.     

The X-ray investigation of 16 alpha,17 alpha-thiazolidine derivatives of delta 4- and delta 5-pregnanes and conformational analysis of their oxathiolane analog

An X-ray study of 3,20-dioxo-4-pregnene-[16 alpha,17 alpha-d]--2',2'-dimethylthiazolidine (I) and 3 beta-hydroxy-20-oxo-5--pregnene-[16 alpha,17 alpha-d]-2',2'- dimethylthiazolidine (II) has been carried out. Two independent molecules in crystal II have significantly different conformations of the D and E rings, although according to the atom-atom potential calculations the energy of interaction of these molecules with their neighbors in crystal is the same. The calculation of conformational energy of 3,20-dioxo-4-pregnene-[17 alpha,16 alpha-d]-2',2'--dimethyloxathiolane (III) by the molecular mechanics method (MMM) indicates a possibility of existence of two similar conformers also for this molecule. The MMM calculation shows also that the conformation of molecule III (as well as progesterone) with the 17 beta-acetyl group torsion angle C(16)C(17)C(20)0(20) close to -120 degrees is possible.     

Study of the conformational profile of selected unnatural amino acid residues derived from l‐phenylalanine

The present work reports the results of a conformational study performed on seven unnatural amino acid residues and on its natural precursor, investigated by means of computational methods at the molecular mechanics level. Amino acid residues selected for the present study are derivatives of l ‐phenylalanine substituted at the α and/or β carbons. This series is composed of different linear analogs, including α‐methyl, β‐methyl and β‐phenyl substituted with different stereochemistry. Analysis of the Ramachandran maps of the corresponding dipeptides in vacuo reveals their conformational preferences, to be used as guidance for the synthesis of constrained peptide analogs with desired conformational propensities. The available conformational space for every dipeptide is also analysed. Copyright © 1999 European Peptide Society and John Wiley & Sons, Ltd.     

New tubular single-stranded helix of poly-L-amino acids suggested by molecular mechanics calculations: I. Homopolypeptides in isolated environments.

A search was made in terms of molecular mechanics calculation for tubular, or pore-forming, single-stranded helices of poly-L-amino acids. Such a helix was found in the vicinity of (phi, psi, omega) = 81 degrees, 98 degrees, 170 degrees) in the conformational space. It was the 6.2(20) helix of right-handedness. The 6.2(20) helix, here named the "mu helix," had a cylindrical pore along its helical axis. The diameter of the pore was 6.6 A on the basis of the atom centers of carbonyl carbons and amino nitrogens. The left-handed mu helix was less stable than the right-handed counterpart. The conformation energy of the mu helix, expressed relative to that of the alpha helix of the same polypeptide, depended to a great extent on amino acid composition. It varied over a range of a few kilocalories per mol per residue above and below the conformation energy of the alpha helix of the same polypeptide. This marked diversity in the relative conformation energy of the mu helix can be ascribed primarily to the difference in the relative position of alpha-carbons between the mu and the alpha helices. The conformational entropy made only a small contribution, if any, to the relative stability of the mu helix. There was a hydrogen-bonded network of side chains in the mu helices of poly-L-glutamine and poly-L-asparagine.     

Conformational behavior of hyaluronan in relation to its physical properties as probed by molecular modeling

Hyaluronan (HA) is a linear charged polysaccharide whose structure is made up of repeating disaccharide units. Apparently conflicting reports have been published about the nature of the helical structure of HA in the solid state. Recent developments in the field of molecular modeling of polysaccharides offer new opportunities to reexamine the structural basis underlying the formation and stabilization of ordered structures and their interactions with counterions. The conformational spaces available and the low energy conformations for the disaccharide, trisaccharide, and tetrasaccharide segments of HA were investigated via molecular mechanics calculations using the MM3 force field. First, the results were used to access the configurational statistics of the corresponding polysaccharide. A disordered chain having a persistence length of 75 A at 25 degrees C is predicted. Then, the exploration of the stable ordered forms of HA led to numerous helical conformations, both left- and right-handed, having comparable energies. Several of these conformations correspond to the experimentally observed ones and illustrate the versatility of the polysaccharide. The double stranded helical forms have also been explored and theoretical structures have been compared to experimentally derived ones.     

Peptides from chiral C alpha,alpha-disubstituted glycines. Synthesis and characterization, conformational energy computations and solution conformational analysis of C alpha-methyl, C alpha-isopropylglycine [(alpha Me)Val] derivatives and model peptides.

Conformational energy computations on Ac-L-(alpha Me)Val-NHMe indicate that turns and right-handed helical structures are particularly stable conformations for this chiral C alpha-methyl, C alpha-alkylglycyl residue. We have synthesized and characterized a variety of L-(alpha Me)Val derivatives and peptides (to the pentamer level). The results of the solution conformational analysis, performed using infrared absorption, 1H nuclear magnetic resonance, and circular dichroism, are in general agreement with those obtained from the theoretical investigation, in the sense that the L-(alpha Me)Val residue turns out to be a strong beta-turn and right-handed helix former. A comparison is also made with the conclusions extracted from published work on peptides rich in other C alpha-methyl, C alpha-alkylglycyl residues.     

Local interactions in peptides. 1H-1H, 13C-H coupling constants and calculations for the conformational analysis of N-acetyl-N'-methylamides of aliphatic amino acids

We report the results of a joint NMR and theoretical investigation devoted to the conformational properties of N-acetyl-N'-methylamides of aliphatic amino acids with side chains of increasing bulkiness: Gly, Ala, Leu, Ile, and tert.Leu. In this series, determination of the coupling constants 3JHNC alpha H together with the coupling constants 3JC'NC alpha H (thanks to specific carbon-13 labeling of the N-acetyl carbonyl group) led to the derivation of alternative A, B, and C parameters in a Karplus-type relation expressing the dependence of 3JC'NC alpha H upon the phi dihedral angle. The value of the latter is found to increase regularly following the increase of the side-chain bulkiness. The theoretical conformational analysis is performed by applying the SIBFA procedure, which uses empirical formulas based on ab initio SCF computations. The conformational energy maps illustrate the progressive distortion of the backbone conformation incurred in the series Gly to tert.Leu. Theoretical values computed for 3JHNC alpha H and 3JC'NC alpha H are found to be in a good quantitative agreement with the experimental ones.     

Conformational analysis and aqueous hydration studies of model peptides for the adhesive protein of the mussel, Mytilus edulis L

Conformations of model peptides of the adhesive protein of the mussel, Mytilus edulis L were investigated using molecular mechanics. The protein structure was represented as the repeat of a 10-residue unit. This decamer, and di- and tri-decamers of it, were considered in the modeling. Incorporation of the unusual dopamine residue in the decamer repeat may be explained by its hydrogen bond forming ability via its 3-OH group to a proline carbonyl oxygen. This bond contributes to maintaining a double reverse beta-turn structure in the decamer. This conformation was found more stable than 3(1) and alpha helical conformations. Adjacent reverse beta-turn structures are connected by short segments (2 to 3 residues) having little conformational preference. Thus, the overall protein can possess a significant random nature, yet have a highly ordered embedded conformational component. Hydrophilic character is in line with the larger number of OH groups on the phenyl ring for residue 9 (the site of the Dopa residue). The dehydration free energy of the (3-OH)-Phe as compared to the Dopa derivative is less by 1.4 kcal per decamer unit. This amounts to more than 100 kcal energy gain in the dehydration process for the total protein.     

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.     

Efficient modelling protocols for oligosaccharides: from vacuum to solvent

The determination of conformational preferences of oligosaccharides is best approached by describing their preferred conformations on potential energy surfaces as a function of the glycosidic linkage φ, ψ torsional angles. For proper molecular mechanics modelling the flexibility of the rotatable pendant groups must also be considered. The so called adiabatic maps partially mimic the flexibility within the 10 dimensional conformational space of the pendant groups of the given disaccharide. These molecular mechanics maps are considered to be the state-of-the art of the φ, ψ potential energy surface of disaccharides recently calculated. The RAMM (RAndom Molecular Mechanics) method was shown to be able to calculate such profiles automatically. Additionally, based on the continuum solvent approach, RAMM allows the calculation of the effects of solvent on conformational energy profiles. Molecular dynamics simulations are also useful tools to study the influence of solvent on conformational behaviour of oligosaccharides. The capability of the RAMM calculational protocol to locate low-energy conformers on the multidimensional potential energy hypersurfaces of disaccharides is illustrated and compared with molecular dynamics simulations with and without inclusion of the solvent. This revised version was published online in August 2006 with corrections to the Cover Date.     

Parallel double helices of DNA. Conformational analysis of regular helices with the second order symmetry axis

We have performed a conformational analysis of DNA double helices with parallel directed backbone strands connected with the second order symmetry axis being at the same time the helix axis. The calculations were made for homopolymers poly(dA).poly(dA), poly(dC).poly(dC), poly(dG) poly(dG), and poly(dT).poly(dT). All possible variants of hydrogen bonding of base pairs of the same name were studied for each polymer. The maps of backbone chain geometrical existence were constructed. Conformational and helical parameters corresponding to local minima of conformational energy of "parallel" DNA helices, calculated at atom-atom approximation, were determined. The dependence of conformational energy on the base pair and on the hydrogen bond type was analysed. Two major conformational advantageous for "parallel" DNA's do not depend much on the hydrogen-bonded base pair type were indicated. One of them coincided with the conformational region typical for "antiparallel" DNA, in particular for the B-form DNA. Conformational energy of "parallel" DNA depends on the base pair type and for the most part is similar to the conformational energy of "antiparallel" B-DNA.     

Parallel Double Helices of DNA. Conformational Analysis of Regular Helices with the Second Order Symmetry Axis

Abstract

We have performed a conformational analysis of DNA double helices with parallel directed backbone strands connected with the second order symmetry axis being at the same time the helix axis. The calculations were made for homopolymers poly(dA) · poly(dA), poly(dC) · poly(dC), poly(dG) poly(dG), and poly(dT) · poly(dT). All possible variants of hydrogen bonding of base pairs of the same name were studied for each polymer. The maps of backbone chain geometrical existence were constructed. Conformational and helical parameters corresponding to local minima of conformational energy of “parallel” DNA helices, calculated at atom-atom approximation, were determined. The dependence of conformational energy on the base pair and on the hydrogen bond type was analysed. Two major conformational advantageous for “parallel” DNA's do not depend much on the hydrogen-bonded base pair type were indicated. One of them coincided with the conformational region typical for “antiparallel” DNA in particular for the B-form DNA Conformational energy of “parallel” DNA depends on the base pair type and for the most part is similar to the conformational energy of “antiparallel” B-DNA.     

Molecular mechanics studies on the conformations of 2',3'-dideoxy-2',3'-didehydroguanine nucleoside, D4G.

Conformational energy calculations have been presented on guanine nucleoside in which the furanose ring is replaced by 2',3'-dideoxy-2',3'-didehydrofuran using molecular mechanics and conformational analysis. Conformational energies have been evaluated using the MM2 and AMBER94 force field parameters at two different dielectric constants. The results are presented in terms of isoenergy contours in the conformational space of the glycosidic (chi) and C4'-C5' (gamma) bonds torsions. In general, the chi-gamma interrelationships differ from the corresponding plots for unmodified nucleosides and nucleotides, reported previously. Consistency of the calculated preferred conformations with the x-ray data is sensitive to the force field employed.     

Conformational Studies on Nucleosides with Furanose Ring Modifications. 1.

Abstract

Conformational energy calculations have been presented on adenine and thymine nucleosides in which the furanose ring is replaced by 2′,3′-dideoxy-2′,3′-didehydrofuran using molecular mechanics and conformational analysis. Conformational energies have been evaluated using the MM2 and AMBER94 force field parameters at two different dielectric constants. The results are presented in terms of isoenergy contours in the conformational space of the glycosidic (χ) and C4′-C5′ (γ) bonds torsions. In general, the χ-γ interrelationships exhibit similarities with the corresponding plots for unmodified nucleosides and nucleotides, reported previously. Consistency of the calculated preferred conformations with the X-ray data is sensitive to the force field employed.     

Comparison of helix-stabilizing effects of alpha,alpha-dialkyl glycines with linear and cycloalkyl side chains

The ability of alpha, alpha-di-n-alkyl glycines with linear and cyclic alkyl side chains to stabilize helical conformations has been compared using a model heptapeptide sequence. The conformations of five synthetic heptapeptides (Boc-Val-Ala-Leu-Xxx-Val-Ala-Leu-OMe, Xxx = Ac8c, Ac7c, Aib, Dpg, and Deg, where Ac8c = 1-aminocyclooctane-1-carboxylic acid, Ac7c = 1-aminocycloheptane-1-carboxylic acid, Aib = alpha-aminoisobutyric acid, Dpg = alpha,alpha-di-n-propyl glycine, Deg = alpha,alpha-di-n-ethyl glycine) have been investigated. In crystals, helical conformations have been demonstrated by x-ray crystallography for the peptides, R-Val-Ala-Leu-Dpg-Val-Ala-Leu-OMe, (R = Boc and acetyl). Solution conformations of the five peptides have been studied by 1H-nmr. In the apolar solvent CDCl3, all five peptides favor helical conformations in which the NH groups of residues 3-7 are shielded from the solvent. Successive NiH<-->Ni + 1H nuclear Overhauser effects over the length of the sequence support a major population of continuous helical conformations. Solvent titration experiments in mixtures of CDCl3/DMSO provide evidence for solvent-dependent conformational transitions that are more pronounced for the Deg and Dpg peptides. Solvent-dependent chemical shift variations and temperature coefficients in DMSO suggest that the conformational distributions in the Deg/Dpg peptides are distinctly different from the Aib/Acnc peptides in a strongly solvating medium. Nuclear Overhauser effects provide additional evidence for the population of extended backbone conformations in the Dpg peptide, while a significant residual population of helical conformations is still detectable in the isomeric Ac7c peptide in DMSO.