DFT studies on the intrinsic conformational properties of non-ionic pyrrolysine in gas phase

B3LYP/6-31G(d,p) level of theory is used to carry out a detailed gas phase conformational analysis of non-ionized (neutral) pyrrolysine molecule about its nine internal back-bone torsional angles. A total of 13 minima are detected from potential energy surface exploration corresponding to the nine internal back-bone torsional angles. These minima are then subjected to full geometry optimization and vibrational frequency calculations at B3LYP/6-31++G(d,p) level. Characteristic intramolecular hydrogen bonds present in each conformer, their relative energies, theoretically predicted vibrational spectra, rotational constants and dipole moments are systematically reported. Single point calculations are carried out at B3LYP/6-311++G(d,p) and MP2/6-31++G(d,p) levels. Six types of intramolecular H-bonds, viz. O…H–O, N…H-O, O…H–N, N…H–N, O…H–C and N…H–C, are found to exist in the pyrrolysine conformers; all of which contribute to the stability of the conformers. The vibrational frequencies are found to shift invariably toward the lower side of frequency scale corresponding to the presence of intramolecular H-bond interactions in the conformers.     

Conformational characteristics of the trinucleoside diphosphate d(ApApA) from energy-minimization studies

Energy-minimization studies were carried out on the trinucleoside diphosphate d(ApApA). The potential energy contributions from nonbonded, electrostatic, hydrogen-bonding, and torsional interactions were minimized by treating the 13 relevant dihedral angles as simultaneous variables. For the C(3′)-endo trimer, 14 low-energy conformations are within 10 kcal/mol above the lowest energy found, compared to only 3 in the case of the C(2′)-endo trimer. This result shows the flexible character of the C(3′)-endo unit. The hairpin-type, loop-promoting conformer with (ω′,ω) = (101°, 59°) was found to be the most favored structure at the 3′-terminus of d(ApApA). The predicted U- and L-type bend conformers were found to lie within 5 kcal/mol, compared to the lowest energy B-DNA structure. The A-DNA and Watson-Crick DNA types of helical conformers also lie within very small energy barriers. The phosphate group at the 5′-end of the nucleotide residue has a definite influence on the base of the corresponding nucleotide, keeping it in the normal anti-region, and hence on the base-stacking property. The results are compared with the presently available experimental data, mainly with the tRNA^Phe crystal.     

Flexibility of 3′,5′ Deoxyribonucleooside Diphosphates

Abstract

In 3′,5′ deoxyribonucleoside diphosphates, in addition to the nature of the base and the sugar puckering, there are six single bond rotations. However, from the analysis of crystal structure data on the constituents of nucleic acids, only three rotational angles, that are about glycosyl bond, about C4′-C5′ and about C3′-O3′ bonds, are flexible. For a given sugar puckering and a base, potential energy calculations using non-bonded, electrostatic and torsional functions were carried out by varying the three torsion angles. The energies are represented as isopotential energy surfaces. Since the availability of the real-time color graphics, it is possible to analyse these isopotential energy surfaces. The calculations were carried out for C3′ exo and C3′ endo puckerings for deoxyribose and also for four bases. These calculations throw more light not only on the allowed regions for the three rotational angles but also on the relationships among them. The dependence of base and the puckering of the sugar on these rotational angles and thereby the flexibility of the 3′,5′ deoxyribonucleoside diphosphates is discussed. From our calculations, it is now possible to follow minimum energy path for interconversion among various conformers.     

A conformational analysis of biologically active RGD-containing cyclopentapeptides

The theoretical conformational analysis of the biologically active RGD-containing pentapeptide cyclo(-Arg-Gly-Asp-Phe-DVal-), an inhibitor of laminin P1 interaction with its receptor, was performed. The space of permissible torsional angles of the backbone of the molecule was studied by the Monte Carlo method. From the large number of predicted low-energy conformers with various packings of the cyclic moiety of this pentapeptide, only those were selected that corresponded to stable structures of the model linear tripeptide Ac-Ala-Gly-Asp-NHMe. This peptide simulated the spatial possibilities of the backbones of RGD-containing fragments of laminin, vitronectin, and fibronectin. We selected several dozen structures that may be potential biologically active conformers, but only a few of them were capable of forming stable intramolecular hydrogen bonds. We assumed that a biologically active conformer of cyclo(-Arg-Gly-Asp-Phe-DVal-) can be present in significant amounts in an equilibrium mixture in solution along with other conformers without necessarily dominating among them.     

Conformational analysis of the biologically active RGD-containing anti-adhesive peptide cyclo(ArgGlyAspPhe-D-val)

Using theoretical conformational analysis, the RGD-peptide with anti-adhesive activity cyclo(ArgGlyAspPhe-D-Val) was studied. Random sampling was used to search the conformational space of the allowed torsional angles of the main chain of the molecule. Among 900 stable conformers with different folding of the cyclic moiety of the peptide, only those were selected which corresponded to low-energy conformers of the model linear tripeptide AcAlaGlyAspNHMe. This peptide served as the main chain template of the RGD-fragment of the studied cyclopeptide molecule. Of 36 selected cyclopeptide conformers with potential biological activity, only a few contain stable intramolecular hydrogen bonds. It was supposed that a biologically active conformer of the cyclopeptide molecule exists in solution among other conformers, but not necessarily as the major component of the equilibrium mixture.     

Flexibility of the pyrrolidine ring in proline peptides

A survey of over 50 crystal structures indicates that both imino acid and peptide derivatives of proline populate ring conformers consistent with the torsional potentials about single bonds. In both cases, lower barriers for rotation about C? N bonds relative to those about C? C bonds favor smaller values for dihedral angles about the former bonds. In peptides a minimum in the torsional potential about C? N bonds occurs at zero dihedral angle, further favoring small angles. The pyrrolidine-ring dihedral angles of the proline compounds in the solid state obey a cyclopentane-type pseudorotation function. Thus the puckering of the five-membered ring can be quantitatively described by two parameters. Consistent with small dihedral angles about C? N bonds, C^β and/or C^γ are puckered out of the mean plane of the ring in nearly all of the nonstrained compounds. Utilizing the consistent force-field method of Lifson and coworkers [see A. Warshel, M. Levitt, and S. Lifson (1970) J. Mol. Spectrosc. 33 , 84] the intramolecular energy of five proline peptides was minimized with respect to all internal coordinates. In addition, the energy surface near minima was explored by constraining a particular dihedral angle and reminimizing the energy with respect to all remaining variables. In linear peptides two types of pyrrolidine-ring conformers have identical predicted energies. In the cyclic dipeptide cyclo (Pro-Gly) one of the ring conformers is favored by about 3 kcal/mol, while the cyclic tripeptide cyclo(Pro-Gly-Gly) favors the other conformer by a comparable margin. In agreement with observations in the solid state and in solution, C^β and/or C^γ are puckered in the predicted conformers. A correlation between proline Φ and the details of the puckered conformation was predicted and found to match precisely conformers observed in crystals. For the diamides N-acetyl-L -proline-N′-methyl-amide and N-acetyl-L -proline-N′,N′-dimethylamide (AcProMe₂A) 30% and 60% cis acetyl peptide bonds were predicted in good agreement with observations in nonpolar solvents for the respective compounds. The conformational distributions with respect to proline Ψ are also in accord with experimental observations. For AcProMe₂A, a model for a -Pro-Pro-sequence in a peptide chain, this study is the first to predict stable conformers for proline Ψ either ca. ?50° or 140° for both cis and trans peptides.     

Conformational analysis of biologically active RGD-containing cyclopentapeptides

The theoretical conformational analysis of the biologically active RGD-containing pentapeptide cyclo(-Arg-Gly-Asp-Phe-DVal-), an inhibitor of laminin P1 interaction with its receptor, was performed. The space of permissible torsional angles of the backbone of the molecule was studied by the Monte Carlo method. From the large number of predicted low-energy conformers with various packings of the cyclic moiety of this pentapeptide, only those were selected that corresponded to stable structures of the model linear tripeptide Ac-Ala-Gly-Asp-NHMe. This peptide simulated the spatial possibilities of the backbones of RGD-containing fragments of laminin, vitronectin, and fibronectin. We selected several dozen structures that may be potential biologically active conformers, but only a few of them were capable of forming stable intramolecular hydrogen bonds. We assumed that a biologically active conformer of cyclo(-Arg-Gly-Asp-Phe-DVal-) can be present in significant amounts in an equilibrium mixture in solution along with other conformers without necessarily dominating among them.     

Conformational Analysis of the 3′-5′-Cyclic Dinucleotide d<pApA> by Means of Molecular Mechanics

Abstract

The conformational properties of the cyclic dinucleotide d<(pApA)> were studied by means of molecular mechanics calculations in which a multiconformation analysis was combined with minimum energy calculations. In this approach models of possible conformers are built by varying the torsion angles of the molecule systematically. These models are then subjected to energy minimization; in the present investigation use was made of the AMBER Force field. It followed that the lowest energy conformer has a pseudo-two-fold axis of symmetry. In this conformer the deoxyribose sugars adopt a N-type conformation. The conformation of the sugar-phosphate backbone is determined by the following torsion angles: α⁺, β¹, γ⁺, ?¹ and ζ⁺. The conformation of this ringsystem corresponds to the structure derived earlier by means of NMR spectroscopy and X-ray diffraction. The observation of a preference for N-type sugar conformations in this molecule can be explained by the steric hindrance induced between opposite H3′ atoms when one sugar is switched from N- to S-type puckers. The sugars can in principle switch from N- to S-type conformations, but this requires at least the transition of γ⁺ to γ^?. In this process the molecule obtains an extended shape in which the bases switch from a pseudo-axial to a pseudo-equatorial position. The calculations demonstrate that, apart from the results obtained for the lowest energy conformation, the 180° change in the propagation direction of the phosphate backbone can be achieved by several different combinations of the backbone torsion angles. It appeared that in the low energy conformers five higher order correlations are found. The combination of torsion angles which are involved in changes in the propagation direction of the sugar-phosphate backbone in DNA-hairpin loops and in tRNA are found in the dataset obtained for cyclic d<(pApA)>. It turns out that in the available examples, 180° changes in the backbone direction are localized between two adjacent nucleotides.     

The HF-SCF energy of HIV-1 MNgp120 V3 hairpin loop conformers

The purpose of this study is to analyze the structure of the V3 loop of the HIV-1 gp120 molecule at the atomic level. The total energy of each member of the antibody-complexed 16-mer V3 conformer data set of Sharon et al. (PDB 1NJ0) was determined by the Hartree–Fock-self-consistent field (HF-SCF) method and with the GROMOS96 force field. There was no correlation between the results of the classical GROMOS96 force field analysis and the ab initio HF-SCF quantum mechanical analysis of the energy of the V3-loop-peptide conformers. HF-SCF optimization (AM1) of conformer geometries yielded structures in which HIS315 is displaced from its original position in the combining site of human antibody fragment 447-52D, but with the hairpin turn intact. The hairpin shape of the V3 loop remained detectable, albeit distorted, even with perturbation by a lithium dicationic electrostatic force field and by substitution of the PRO320 at the crown of the V3 hairpin by a GLY. These data suggest that the hairpin conformation is at least partially stable to long-range electrostatic perturbations, either with or without PRO in the tip of the crown of the V3-hairpin loop. Figure Molecular geometry of HIV-1 V3 conformer model 5 and a GLY320 substituted model 5. Space-filling models were obtained with ViewMol3D [Sharon et al. (2002) PDB 1NJ0]). Red=oxygen, blue=nitrogen, black=carbon, white=hydrogen and purple=lithium. End-to-end distance (D) was obtained with ViewMol3D and is in Ångströms. Geometry optimized GLY320 Model 5, D=4.74 ÅThis revised version was published online in October 2004 with corrections to the Graphical Abstract.     

Alternate g−g−. conformation for dinucleoside phosphates in solution

An alternative g^?g^? conformation (conformer I') for dinucleosides in solution has been deduced, based on potential energy calculations and nuclear magnetic resonance spectroscopy. This conformation is characterized by larger glycosidic torsional angles (X=94–111°) than those of conformer 1 (X=8–35°), although the other torsional angles are similar. There are thus four stable confonners (I, I', II and III) for dinucleosides in equilibrium with the open forms. The structure of conformer I' supports that of the ‘vertical’ double helix constructed by Olson (W.K. Olson. Proc. Natl. Acad. Sci. U.S.A. 74, (1977) 1775). Our data may suggest the possibility of interconversion between the vertical double helix and the regular double helix of A-form DNA, RNA or A'-form RNA.     

Theoretical studies on sulfanilamide and derivatives with antibacterial activity: conformational and electronic analysis

Quantum chemical methods have been used to study the conformational and electronic properties of sulfanilamide and derivatives with antibacterial activity. Calculations at B3LYP/6-311++G(3df,2p) level of theory predict the existence of four conformers for sulfanilamide depending on the orientation of p-amino and amide groups. Focusing on the sulfonamide moiety, amide NH₂ and SO₂ groups could exist either in an eclipsed or staggered arrangement. Gas-phase results predict the eclipsed conformer to be most stable but opposite to what has been rationalized previously, no stabilizing hydrogen bonds between those groups has been found through NBO analysis. When solvent effect is taken into account through the IEF-PCM method, staggered conformer is preferred; in fact, eclipsed conformation changed when explicit solvent molecules were included. Conformational analysis of all derivatives has shown two global minima which are specular images. Five out of the seven derivatives studied adopted a particular minimum energy conformation with very similar geometries.     

Quantitative pressure injection of picoliter volumes into Limulus ventral photoreceptors.

The conformation of the 14 amino acid peptide hormone somatostatin in aqueous solution was investigated through a proton magnetic resonance (PMR) scalar coupling analysis. Experiments were performed at two fields, 270 and 600 MHz, and included double and triple resonance difference scalar decoupling, resolution enhancement and computer simulation. The agreement between simulated and observed spectra at both fields provided support for the correctness of the analysis. The resultant scalar coupling constants, 3J alpha H-NH and 3J alpha B, gave information on the backbone (phi) and side chain (chi 1) torsional angles, respectively, which eliminated either of the proposed conformations of somatostatin as describing a predominant conformer of the molecule in solution under our conditions.     

Stabilization of the Bio-membrane by Small Molecules: Interaction of Trehalose with the Phospholipid Bilayer

Abstract

Anhydrobiotic organisms undergo periods of acute dehydration during their life cycle. It is of interest to understand how the biomembrane remains intact through such stress. A di-saccharide, trehalose, which is metabolised during anhydrobiosis is found to prevent disruption of model membrane systems (1). Molecular modelling techniques are used to investigate the possible mode of interaction of trehalose with a model monolayer. The objective is to maximise hydrogen bonding between the two systems. A phospholipid matrix consisting of l,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) is chosen to represent the monolayer. The crystal structure of DMPC (2) reveals that there are two distinct conformers designated as A and B. An expansion of the monolayer, coplanar with its surface, results in the trehalose molecule being accomodated in a pocket formed by four B conformers. One glucose ring of the sugar rests on the hydrophobic patch provided by the choline methyls of an A conformer. Five hydrogen bonds are formed involving the phosphate oxygens of three of the surrounding B conformers. The model will be discussed with reference to relevant experimental data on the interaction.     

Enantiomeric conformers of the opioid agonist ketobemidone HCl in the crystal state

A crystal of the potent opioid agonist ketobemidone [1-methyl-4-(3-hydroxyphenyl)-4-propionylpiperidine] HCl was analyzed by X-ray crystallography. The crystal was monoclinic, space group P2₁/n with four molecules in the unit cell. In agreement with MM2 calculations (J. Med. Chem. 25:1127–1133, 1982), the crystal contains mirror image conformers in which the phenyl ring is equatorial to the piperidine ring. The conformers are enantiomers since they are not superimposable. One conformer is predicted to be responsible for the typical morphine-like activity of the compound since it closely matches the preferred conformer of the morphine-like (+)-phenylmorphan whereas the other conformer resembles the preferred conformers of (+)-β-prodine and (?)-phenylmorphan which have atypical opioid properties and/or structure–activity relationships. The importance of considering the conformational enantiomers of a nonchiral receptor ligand in centrosymmetric crystal structures is emphasized. © 1993 Wiley-Liss, Inc.     

Molecular docking, 3D-QSAR,molecular dynamics,synthesis and anticancer activity of tyrosine kinase 2 (TYK 2) inhibitors

Abstract

A therapeutic rationale is proposed by selectively targeting tyrosine kinase 2 (TYK 2) to obtain potent TYK 2 inhibitors by molecular modeling studies. In the present study, we have taken tyrosine kinase (TYK 2) inhibitors and carried out molecular docking, 3?D quantitative structure–activity relationship (3D-QSAR) analysis and molecular dynamics (MD). Based on the 3D-QSAR results thirteen new compounds (R-1 to R-13) were designed and synthesized in good yields. The synthesized molecules were evaluated for their in vitro anticancer activity against LnCap and A549 cell lines. The molecules R-1, R-3, R-5, R-7, and R-10 exhibited considerable anti cancer activity.     

Conformational-energy calculations for oligosaccharides: a comparison of methods and a strategy of calculation

A theoretical conformational analysis of dimethoxymethane, 2-methoxytetrahydropyran, cellobiose, and maltose has been performed. The validity of several commonly used classical approaches to conformational energy, assuming non-bonded interactions, torsional terms, and the exo-anomeric contribution, and the MM2CARB method (a modified version of the MM2 force-field program using the Jeffrey-Taylor parameters) was tested against available experimental data or previous quantum-chemical calculations. The MM2CARB method correctly reproduces the energies and the variations in bond lengths and bond angles for conformers of dimethoxymethane and 2-methoxytetrahydropyran. Prediction of the observed conformers with simple potential functions appears to be less satisfactory. In particular, calculations that take into account non-bonded interactions and the exo-anomeric contribution based on dimethoxymethane give predicted energy differences that are 2–3 times higher than the experimental values. The general shapes of the (Φ, Ψ) potential-energy surfaces for cellobiose and maltose provided by potential-function calculations suggest the presence of several minima whose energies depend, to a great extent, on the choice of molecular geometry. The MM2CARB-calculated structures of seven cellobiose and five maltose conformers demonstrate clearly the variation of disaccharide geometry with change of conformation around the glycosidic linkage. The relative energies calculated by simple methods differ from MM2CARB energies and indicate that the simple potential-functions methods give only a qualitative estimate of oligosaccharide conformers. Based on these results, we propose a general strategy and two different approaches for the investigation of conformational properties of oligosaccharides.     

Predominant torsional forms adopted by dipeptide conformers in solution: parameters for molecular recognition.

The present paper describes the predominant conformational forms adopted by dipeptides in aqueous solution. More than 50 dipeptides were subjected to conformational analysis using SYBYL Random Search. The resultant collections of conformers for individual dipeptides, for small groups with related side chain residues and for large groups of about 50 dipeptides were visualized graphically and analysed using a novel three-dimensional pseudo-Ramachandran plot. The distribution of conformers, weighted according to the percentage of each in the total conformer pool, was found to be restricted to nine main combinations of backbone psi (psi) and phi (phi) torsion angles. The preferred psi values were in sectors A7 (+150 degrees to +/-180 degrees), A10 (+60 degrees to +90 degrees) and A4 (-60 degrees to -90 degrees), and these were combined with preferred phi values in sectors B12 (-150 degrees to +/-180 degrees), B9 (-60 degrees to -90 degrees) and B2 (+30 degrees to +60 degrees). These combinations of psi and phi values are distinct from those found in common secondary structures of proteins. These results show that although dipeptides can each adopt many conformations in solution, each possesses a profile of common conformers that is quantifiable. A similarly weighted distribution of dipeptide conformers according to distance between amino-terminal nitrogen and carboxyl-terminal carbon shows how the preferred combinations of backbone torsional angles result in particular N-C geometries for the conformers. This approach gives insight into the important conformational parameters of dipeptides that provide the basis for their molecular recognition as substrates by widely distributed peptide transporters. It offers a basis for the rational design of peptide-based bioactive compounds able to exploit these transporters for targeting and delivery.     

The analysis of structure-anticancer and antiviral activity relationships for macrocyclic pyridinophanes and their analogues on the basis of 4D QSAR models (simplex representation of molecular structure)

A new 4D-QSAR approach has been considered. For all investigated molecules the 3D structural models have been created and the set of conformers (fourth dimension) have been used. Each conformer is represented as a system of different simplexes (tetratomic fragments of fixed structure, chirality and symmetry). The investigation of influence of molecular structure of macrocyclic pyridinophanes, their analogues and certain other compounds on anticancer and antiviral (anti-influenza, antiherpes and antiadenovirus) activity has been carried out by means of the 4D-QSAR. Statistic characteristics for QSAR of PLS (partial least squares) models are satisfactory (R = 0.92-0.97; CVR = 0.63-0.83). Molecular fragments increasing and decreasing biological activity were defined. This information may be useful for design, and direct synthesis of novel anticancer and antiviral agents.