Experimental investigations on the backbone folding of proline-containing model tripeptides

Some proline-containing tripeptides with the general formulas R⁰CO-L -Pro-X-NHR³ (X = Gly,Sar,L -Ala,D -Ala) and R⁰CO-X-L -Pro-NHR³ (X = Gly,L -Ala,D -Ala) have been investigated in solution by ir and ¹H-nmr spectroscopies. Their favored conformational states depend mainly on both the primary structure and the chiral sequence of the molecules. In inert solvents the βII-folding mode is the most favored conformation for the L -Pro-D -Ala and L -Pro-Gly tripeptides, while the βII′-turn is largely preferred by D -Ala-L -Pro derivatives. Under the same conditions only about one-third of the whole conformers of L -Pro-L -Ala molecules adopts the βI-folding mode. Semiopened C₇C₅ and C₅C₇ conformations are appreciably populated in the L -Pro-L -Ala sequence, on the one hand, and in the Gly-L -Pro and L -Ala-L -Pro derivatives, on the other hand. In L -Pro-Sar and X-L -Pro models, the cis–trans isomerism around the middle tertiary amide function is observed. Thus cis L -Pro-Sar and L -Ala-L -Pro conformers are folded by an intramolecular i + 3 → i hydrogen bond, whereas cis D -Ala-L -Pro and Gly-L -Pro molecules accommodate an open conformation. In dimethylsulfoxide the βII- and βII′-folding modes are not essentially destabilized, as contrasted with the βI conformation, which is less populated. In water solution all the above-mentioned conformations, with the possible exception of the βII′-folding mode for D -Ala-L -Pro molecules, seem to vanish. Solute conformations are also compared with the crystal structures of four proline-containing tripeptides.     

Flexibility of the pyranose ring in α- and β-D-glucoses

Conformational energies of α- and β-D -glucopyranoses were computed by varying all the ring bond angles and torsional angles using semiempirical potential functions. Solvent accessibility calculations were also performed to obtain a measure of solvent interaction. The results indicate that the ⁴C₁ (D ) chair is the most favored conformation, both by potential energy and solvent accessibility criteria. The ⁴C₁ (D ) chair conformation is also found to be somewhat flexible, being able to accommodate variations up to 10° in the ring torsional angles without appreciable change in energy. Observed solid-state conformations of these sugars and their derivatives lie in the minimum-energy region, suggesting that the substituents and crystal field forces play a minor role in influencing the pyranose ring conformation. Theory also predicts the variations in the ring torsional angles, i.e., CCCC < CCCO < CCOC, in agreement with the experimental results. The boat and twist-boat conformations are found to be at least 5 kcal mol^?1 higher in energy compared to the ⁴C₁ (D ) chair, suggesting that these forms are unlikely to be present in a polysaccharide chain. The ¹C₄ (D ) chair has energy intermediate between that of the ⁴C₁ (D ) chair and that of the twist-boat conformation. The calculated energy barrier between ⁴C₁ (D ) and ¹C₄ (D ) conformations is high—about 11 kcal mol^?1.     

Raman spectra of polypeptides containing L-histidine residues and tautomerism of imidazole side chain

Raman spectra were measured for poly(L -histidine) in H₂O, poly(L -histidine-d₂ and -d₃) in D₂O, L -histidine in H₂O, L -histidine-d₃ (and d₄) in D₂O, and 4-methylimidazole in H₂O with various pH (or pD) values. The Raman scattering peaks observed for these samples were ascribed to the neutral and positively charged imidazole groups on the basis of the spectral changes due to the pH variation and to the deuterium substitution of the imino protons. The vibrational modes of these peaks were deduced from the normal coordinate analysis made on the positively charged and neutral 4-ethylimidazoles. The Raman scattering peaks from the imidazole groups in the neutral form clearly indicate that these imidazole groups exist in the equilibrium between the two tautomeric forms, the 1-N protonated from (tautomer I) and the 3-N protonated one (tautomer II). For example, the breathing vibration of the 1-N protonated form is observed at 1282 cm^?1 for L -histidine and at 1304 cm^?1 for 4-methylimidazole, while the breathing vibration of the 3-N protonated form is observed at 1260 cm^?1 for L -histidine and 4-methylimidazole. From the temperature dependence of the relative intensities of the tautomer I peak to that of the tautomer II, it was concluded that the tautomer I is energetically more stable than the tautomer II, and the ΔH value is 1.0 ± 0.3 kcal/mol for L -histidine and 0.4 ± 0.1 kcal/mol for 4-methylimidazole. Poly(L -histidine) with the neutral imidazole side chains shows the amide I peak at 1672 cm^?1, indicating that the sample assumes the antiparallel pleated-sheet structure. Poly(L -Ala⁷⁵L -His²⁵) and poly(L -Ala⁵⁰L -His⁵⁰) were found to take the α-helical and β-form conformations, respectively.     

Crystal structure and conformation of a cyclic tetrapeptide cyclo(L-Pro-Sar)2 containing all-cis peptide units

The crystal structure and conformation of the synthetic cyclic tetrapeptide, cyclo(L -Pro-Sar)₂, was determined by x-ray analysis. The peptide crystallizes in the orthorhombic space group P2₁2₁2₁ with cell parameters a = 9.277(1), b = 12.884(1), and c = 15.581(2) Å. The crystal structure was solved by the symbolic addition procedure for direct phase determination and least-squares refinement using 1796 reflections, which led to the final R value of 0.043. This structure provides the first example observed in a crystal of a cyclic tetrapeptide in which all four peptide units have been found in the cis conformation with ω angles deviating slightly by 2°–10° from the ideal value of 0°. It was also found that the two Pro C^α-CO single bonds assumed a trans′ (ψ = 159.6° and 158.4°) conformation. Adjoining average planes of the peptide groups fall at nearly right angles to each other. The pyrrolidine ring conformations of the two prolyl residues are in the envelope form, with C^γ carbon out of the least-squares planes for the remaining four atoms.     

Several transition states from C1 to skew conformations of β-d-glucopyranose

The interconversion pathways in the ring distortion of β-d-glucopyranose were investigated using density functional calculations. We examined the energies of several conformers of β-d-glucopyranose and tried to obtain the transition-state conformation and determine the pathway between a ⁴C₁ chair and some distorted ring conformers. The results showed that two E₃/²H₃ conformations and one E₃/⁴H₃ conformation were transition states in such ring puckering. The transition state with the lowest energy conformation is the E₃/²H₃ ring conformation with the side-chain conformation of r-ggG⁺. Intrinsic reaction coordinate calculations indicated that the E₃/²H₃ conformation with the lowest conformational energy is a transition state of the ring interconversion path between the conformations of ⁴C₁ and ²S_O/B_3,O. The energy barrier of this interconversion was 6.13 kcal/mol. As far as we know, this is the first example of finding pathways for an interconversion of glucopyranose ring puckering at the level of a quantum chemical calculation.     

H-nmr study on the preferred conformations of chiral pyridine-dinucleotide models

The synthesis of four chiral NAD⁺ models 1 and their 1,4-dihydro analogs 2 is described. From the temperature dependence of the ¹H-nmr spectra it is concluded that for these compounds two preferred conformations I and II, differing slightly in energy, exist. Both conformations are “folded” with the more or less parallel p-anisyl and pyridine groups mutually gauche, but in I the pyridine group is rotated by about 180° as compared with II, thus leading to a conspicuous difference in orientation of the substituent Z (NH₂CO, C₆H₅NHSO₂, (CH₂)₄NSO₂, or (C₄H₈ON)SO₂) in the pyridine ring toward the anisyl group. The most stable conformation (I) has Z closest to the center of the p-anisyl group. In 360-MHz spectra of the dihydropyridines at low temperature (−10°C), slow interconversion of I and II leads to the observation of an XY pattern for the C-4 methylene protons of the 1,4-dihydropyridine system. The anisochronity in this methylene group is caused mainly by the anisotropy of the neighboring p-anisyl group.     

Conformational energy studies on N-methylated analogs of thyrotropin releasing hormone, enkephalin, and luteinizing hormone-releasing hormone

Empirical conformational energy calculations have been carried out for N-methyl derivatives of alanine and phenylalanine dipeptide models and N-methyl-substituted active analogs of three biologically active peptides, namely thyrotropin-releasing hormone (TRH), enkephalin (ENK), and luteinizing hormone-releasing hormone (LHRH). The isoenergetic contour maps and the local dipeptide minima obtained, when the peptide bond (ω) preceding the N-methylated residue is in the trans configuration show that (1) N-methylation constricts the conformational freedom of both the ith and (i + 1)th residues; (2), the lowest energy position for both residues occurs around ? = ?135° ± 5° and ψ = 75° ± 5°, and (3) the α_L conformational state is the second lowest energy state for the (i + 1)th residue, whereas for the ith residue the C₅ (extended) conformation is second lowest in energy. When the peptide bond (ω_i) is in the cis configuration the ith residue is energetically forbidden in the range ? = 0° to 180° and ψ = ?180° to +180°. Conformations of low energy for ω_i = 0° are found to be similar to those obtained for the trans peptide bond. In all the model systems (irrespective of cis or trans), the α_R conformational state is energetically very high. Significant deviations from planarity are found for the peptide bond when the amide hydrogen is replaced by a methyl group. Two low-energy conformers are found for [(N-Me)His²]TRH. These conformers differ only in the ? and ψ values at the (N-Me)His² residue. Among the different low-energy conformers found for each of the ENK analogs [D -Ala²,(N-Me)Phe⁴, Met⁵]ENK amide and [D -Ala²,(N-Me)Met⁵]ENK amide, one low-energy conformer was found to be common for both analogs with respect to the side-chain orientations. The stability of the low-energy structures is discussed in the light of the activity of other analogs. Two low-energy conformers were found for [(N-Me)Leu⁷]LHRH. These conformations differ in the types of bend around the positions 6 and 7 of LHRH. One bend type is eliminated when the active analog [D -Ala⁶,(M-Me)Leu⁷]LHRH is considered.     

X-ray crystal structure of iridoid glucoside aucubin and its aglycone

X-ray diffraction analyses of iridoid glycoside aucubin (1) and its aglycone aucubigenin (2) are reported. It was found that crystals of 1 are orthorhombic, with P2₁2₁2₁ space group, both cyclopentane ring and pyran ring adopt envelope conformations, and the Glc moiety is in the ⁴C₁ conformation. Crystals of 2 are monoclinic, with space group P2₁, the cyclopentane and pyran rings also adopt the envelope conformation. The absolute configurations of 1 and 2 were also determined. Intensive O–HO hydrogen bonds in both crystal lattices were observed.     

Conformational studies of per-O-trimethylsilyl derivatives of D-fructoses and oligosaccharides containing β-D-fructofuranose residues by 220- and 300-MHz P.M.R. spectroscopy

The interpretation of 220- and 300-MHz P.M.R. spectra and the accurate chemical shifts and coupling constants of a number of per-O-trimethylsilyl-(TMS-) D-fructose derivatives and TMS-oligosaccharides containing β-D-fructofuranose residues are presented. On the basis of calculations with an adapted Karplus equation it is concluded that TMS-α- and -β-D-fructopyranose occur in the ²C₅(D) chair conformation whereas the D-glucopyranose rings in the oligosaccharides adopt the usual ⁴C₁(D) chair conformation. The structure of the latter units is very similar to that of TMS-α-_D-glucopyranose. The ⁴E(D) envelope and ⁴T₅(D) twist are the principal conformations of the D-fructofuranose rings. The conformation of the furanose ring depends on the number and kind of monosaccharide units attached thereto. The calculated, preferred conformation of the C-5-CH₂OTMS group of the D-fructofuranose moieties correlates with the time-averaged displacement of C-4 above the plane of C-2, C-3, and O-5.     

Controlling the helical screw sense of peptides with C‐terminal L‐valine

One chiral L ‐valine (L ‐Val) was inserted into the C‐terminal position of achiral peptide segments constructed from α‐aminoisobutyric acid (Aib) and α,β‐dehydrophenylalanine (Δ^ZPhe) residues. The IR, ¹H NMR and CD spectra indicated that the dominant conformations of the pentapeptide Boc‐Aib‐ΔPhe‐(Aib)₂‐L ‐Val‐NH‐Bn (3) and the hexapeptide Boc‐Aib‐ΔPhe‐(Aib)₃‐L ‐Val‐NH‐Bn (4) in solution were both right‐handed (P) 3₁₀‐helical structures. X‐ray crystallographic analyses of 3 and 4 revealed that only a right‐handed (P) 3₁₀‐helical structure was present in their crystalline states. The conformation of 4 was also studied by molecular‐mechanics calculations. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.     

Conformation of cyclic analogs of enkephalin. II. Analogs containing a cystine bridge

A systematic survey has been made, using molecular mechanics, of the conformation of the ring entity of the enkephalin analogs, [D -Cys²-L -Cys⁵]-enkephalinamide and [D -Cys²-D -Cys⁵]enkephalinamide. These molecules are considerably more flexible than the analog Tyr-cyclo(N^γ-D -A₂bu-Gly-Phe-Leu-), but the favored conformations of all three are very similar. The results of these studies are compatible with a Gly³-Phe⁴ type II′ bend in the active conformation of enkephalin.     

Conformational studies of heterochiral peptides with diastereoisomeric residues: Crystal and molecular structures of linear dipeptides derived from leucine,isoleucine, and allo-isoleucine

The x-ray diffraction analyses of three N- and C-terminally blocked L , D dipeptides, namely t-Boc-D -Leu-L -Leu-OMe ( 1 ), t-Boc-L -Ile-D -alle-OMe ( 2 ), and t-Boc-D -aIle-L -Ile-OMe (3) containing enantiomeric or diastereomeric amino acid residues have been carried out. The structures were determined by direct methods and refined anisotropically to final R factors of 0.077. 0.058. and 0.072 for ( 1 ) ( 2 ) and ( 3 ), respectively. Peptides 1–3 all assume a similar U-shaped structure with ? and ψ torsion angles cosrresponding to one of the possible calculated minimum energy regions (regions E and G for L residues, and F*. D* and H* for D residues). The peptide backbones of 1-3 are almost super-imposable [provided that the appropriate inversion of the chiral centers of ( 2 ) is made]. Side-chain conformations of Leu residues in peptide ( 1 ) are g^? (tg^?) for the L -Leu residue and the mirrored g⁺ (tg⁺) for the D -Leu residue; however, in peptides ( 2 ) and ( 3 ) the conformations of the isoconfiguralional side chains of the Ile or allo-Ile residues are (g^?t) t and (tg⁺) tfor the L -Ile and the D -allo-Ile moieties, respectively. In all cases, these conformations correspond to the more populated conformers of β-branched residues statistically found in crystal structures of small peptides. The results seem to indicate that, at least in short peptides with enantiomeric or diastereoisomeric residues, the change in chirality in the main-chain atoms perturbs the backbone conformation to a lesser extent and the side chain conformation to a greater extent. © 1995 John Wiley & Sons, Inc.     

1H-nmr study on the preferred conformations of chiral pyridine-dinucleotide models

The synthesis of four chiral NAD⁺ models 1 and their 1,4-dihydro analogs 2 is described. From the temperature dependence of the ¹H-nmr spectra it is concluded that for these compounds two preferred conformations I and II, differing slightly in energy, exist. Both conformations are “folded” with the more or less parallel p-anisyl and pyridine groups mutually gauche, but in I the pyridine group is rotated by about 180° as compared with II, thus leading to a conspicuous difference in orientation of the substituent Z (NH₂CO, C₆H₅NHSO₂, (CH₂)₄NSO₂, or (C₄H₈ON)SO₂) in the pyridine ring toward the anisyl group. The most stable conformation (I) has Z closest to the center of the p-anisyl group. In 360-MHz spectra of the dihydropyridines at low temperature (?10°C), slow interconversion of I and II leads to the observation of an XY pattern for the C-4 methylene protons of the 1,4-dihydropyridine system. The anisochronity in this methylene group is caused mainly by the anisotropy of the neighboring p-anisyl group.     

1H and 13C nmr studies of cyclic and linear dipeptides containing threonyl,seryl, aspartyl,and histidyl residues

The side-chain conformations of D - orL - Thr, D - or L -Ser, L -Asp, and L - His residues in cyclic and linear dipeptides in D₂O or in DMSO-d₆ are deduced from vicinal (¹H,¹H) and (¹³C, ¹H) coupling constants. Vicinal (¹³C, ¹³C) coupling constants strongly depend on substituents and cannot be used without a more sound analysis. In cyclic dipeptides, the Thr and Ser side chains are folded above the DKP ring, with χ¹ near 60°. The L -Asp side chain interacts more specifically with peptide bonds (χ¹ near 300°). The L - His side chain is more flexible and its conformation depends on the proximity of a second side chain and on solute-solvent interactions. In all cases, this side chain is not completely folded. In linear dipeptides, the conformation of a C-terminal L -His residue is mainly influenced by the end carboxylic group. On the other hand, a N-terminal L -His residue interacts more easily with a neighboring L -Asp residue. In aqueous solution, the imidazole pK_a depends on the proximity of terminal and lateral charged groups but does not reveal any specific interaction in cyclic dipeptides. A comparison between the conformations of cyclic peptides observed in solution, in the crystalline state and calculated by empirical methods, allows one to point out the discriminating role of the packing in crystals, and of solute-solvent interactions in solution.     

Etude,par spectroscopie infra-rouge,de la conformation de quelques composés peptidiques modèles

Some experimental data are given on the infrared spectra between 3300 and 3500 cm^?1 of dilute solutions in carbon tetrachloride of three types of model compounds: CH_3?CONH-CH(R₁)-CONH(R₂), (I); CH₃-CON(CH₃)-CH(R₁)-CONH(R₂), (II) and CH₃-CONH-CH(R₁)-CON(R₂)₂, (III). In studying the N-H stretching bands, it was found that there are two types of intramolecular hydrogen bonds in these molecules; these result in two different cyclized conformations, C₅ and C₇, which contain respectively, five and seven atoms in the ring. By using model substances I, II, and III, in which the nitrogen atoms are unequally substituted, it is possible to identify the N-H stretching bands which are to be ascribed to the N-H oscillators included in the two different chelated conformations. It is found also that the stretching frequency of a free N-H oscillator depends upon the substituent on the nitrogen atom. Thus, it is possible to observe, with some of the model compounds I, four different absorption bands located at 3340, 3420, 3440, and 3460 cm^?1. The first two are ascribed to the N-H oscillators included in the H? bonds which lock the C₇ and C₅ conformations; the last two correspond to free N-H which differ with the substituent on the nitrogen atom.     

π Delocalization in iridathiabenzenes

Fenske-Hall calculations were carried out for (PEt₃)₃Ir(C₇H₉) (1), [(PEt₃)₃Ir(C₆H₈S)]⁺ (2), [(S-t-but)(PEt₃)₂]Ir(C₆H₈S) (3), and [(S-t-but)(PMet₃)₃]Ir(C₆H₈S) (4) in order to compare the degree of π delocalization in the metallathiacycle rings of (2) and (3). In comparison to (1), a true iridabenzene and (4), an iridathiacyclobutadiene, the π ring systems in (2) and (3) are considerably more localized than the π system in (1) but are not totally localized. Strong metal-sulfur bonding in (2) disrupts the π ring system and results in some localization of the ring π bonds. The introduction of the donor thiolate ligand in (3) disrupts the ring of π system even more by destabilizing the metal orbitals used for metal-sulfur interactions. This weakens the metal-sulfur interaction seen in (2) and leads to even more localization of the ring π system in (3).     

Stereodynamics of Nitrogen Chiral Centers in aza‐β3‐Cyclodipeptides

The present work is devoted to the synthesis, conformational analysis, and stereodynamic study of aza‐β³‐cyclodipeptides. This pseudopeptidic ring shows E/Z hydrazide bond isomerism, eight‐membered ring conformation, and chirotopic nitrogen atoms, all of which are elements that are prone to modulate the ring shape. The (E,E) twist boat conformation observed in the solid state by X‐ray diffraction is also the ground conformation in solution, and emerges as the lowest in energy when using quantum chemical calculations. The relative configuration associated with ring chirality and with the two nitrogen chiral centers is governed by steric crowding and adopts the (P)S_NS_N/(M)R_NR_N combination which projects side chains in equatorial position. The nitrogen pyramidal inversion (NPI) at the two chiral centers is correlated with the ring reversal. The process is significantly hindered as was shown by VT‐NMR experiments run in C₂D₂Cl₄, which did not make it possible to determine the barrier to inversion. Finally, these findings make it conceivable to resolve enantiomers of aza‐β³‐cyclodipeptides by modulating the backbone decoration appropriately. Chirality 25:341–349, 2013. © 2013 Wiley Periodicals, Inc.     

Carrier design: Conformational studies of amino acid (X) and oligopeptide (X-DL-Alam) substituted poly(L-lysine)

The present study was undertaken to examine the influence of the reversal of the sidechain sequential order on the conformation of branched polypeptides. At the same time, the influence of the optically active amino acid joined directly to the poly (L -Lys) backbone and the DL -Ala oligomer grafted as chain-terminating fragment were separately analyzed. Therefore two sets of polypeptides were synthesized corresponding to the general formula poly [Lys-(X_i,)] (XK) and poly[Lys-(DL -Ala_m-X_i)] (AXK) when X = Ala, D -Ala, Leu, D -Leu, Phe, D -Phe, Ile, Pro, Glu.,D -Glu, or His. For coupling amino acid X to polylysine, three types of active ester methods were compared: the use of pentafluorophenyl or pentachlorophenyl ester, and the effect of the addition of an equimolar amount of 1-hydroxybenzotriazole. After cleavage of protecting groups, AXK polypeptides were synthesized by grafting short oligo (DL -Ala) chains to XK by using N-carboxy-DL -Ala anhydride. The CD measurements performed in water solutions of various pH values and ionic strengths were used for classification of the polypeptide conformations as either ordered (helical) or unordered. Different from what was observed with the unsubstituted poly (L -Lys), poly[Lys-(X_i)] type polypeptides can adopt ordered structure even under nearly physiological conditions (pH 7.3, 0.2M NaCl). These data suggest that the introduction of amino acid residue with either (ar) alkyl side chain (Ala, Leu, Phe) or negatively charged side chain (Glu) promotes markedly the formation of ordered structure. Comparison of chiroptical properties of poly [Lys- (DL -Ala_m-X_i)] and of poly [Lys- (X_i)] reveals that side-chain interactions play an important role in the stabilization of ordered solution conformation of AXK type branched polypeptides. The results give rather conclusive evidence that not only hydrophobic interactions, but also ionic attraction, can be involved in the formation and stabilization of helical conformation of branched polypeptides. © 1993 John Wiley & Sons, Inc.     

Conformational energy calculations of enzyme-substrate complexes of lysozyme. I. Energy minimization of monosaccharide and oligosaccharide inhibitors and substrates of lysozyme

Conformational energy calculations were performed on monosaccharide and oligosaccharide inhibitors and substrates of lysozyme to examine the preferred conformations of these molecules. A grid-search method was used to locate all of the low-energy conformational regions for N-acetyl-β-D -glycosamine (NAG), and energy minimization was then carried out in each of these regions. Three stable positions for the N-acetyl group have ben located, in two of which the plane of the amide unit is normal to the mean plane of the pyranosyl ring. Nine local energy minima were located for the —CH₂OH group. The positions of the two vicinal cis —OH groups are determined predominantly by interactions with either the —CH₂OH or the N-acetyl group. The most stable conformations of β-N-acetylmuramic acid (NAM) were determined from the study of the low-energy conformations of NAG. In the two stable orientations for the D -lactic acid side chain, the O—C—C′ plane (C′ being the carbon atom of the terminal carboxyl group) was found to be normal to the mean plane of the pyranosyl ring. The low-energy positions for the COOH group of NAM are determined mainly by interactions with neighboring groups. The conformational preferences of the α-anomers of NAG and NAM were also explored. The calculated conformation of the N-acetyl group for α-NAG was quite close to that determined by X-ray analysis. Two of the three lowest energy conformations of α-NAM are similar to the corresponding conformations of the β-anomer. A third low-energy structure, which has a hydrogen bond from the NH of the N-acetyl group to the C?O of the lactic acid group, corresponds very closely to the X-ray structure of this molecule. The preferred conformations of the disaccharides NAG–NAG, NAM–NAG and NAG–NAM were also investigated. Two preferred orientations of the reducing pyranosyl ring relative to the nonreducing ring were found for all of these disaccharides, both of which are close to the extended conformation. In one of these conformations, a hydrogen bond can form between the OH group attached to C₃ of the reducing sugar and the ring oxygen of the preceding residue. Each conformation can be stabilized further by a hydrogen bond between the CH₂OH (donor) of residue i + 1 and the C?O of residue i (acceptor). The interactions that determine conformations for all oligosaccharides containing both NAG and NAM are shown to be exclusively intraresidue and nearest neighbor interactions, so that it is possible to predict all stable conformations of oligosaccharides containing NAG and NAM in any sequence.     

Modelling of β-d-glucopyranose ring distortion in different force fields: a metadynamics study

Modelling of carbohydrate conformations is a challenging task for force field developers. Three carbohydrate force fields, namely GLYCAM06, GROMOS 45a4 and OPLS were evaluated. Free energies of different ring conformations of β-d-glucopyranose were calculated using metadynamics in vacuum as well as in explicitly modelled water. All three force fields model the ⁴C₁ conformation as the most stable by at least 6 kJ/mol, as compared to other conformations. Interconversion from the ⁴C₁ to any other conformation is associated with a barrier of no lower than 26 kJ/mol. The free energy surface calculated in the GLYCAM06 force field is in remarkably good agreement with the recent Car-Parrinello metadynamics study. The effect of a water environment is relatively low and analogous in all tested force fields. Namely, the presence of water stabilizes the upper-left (^3,OB) versus bottom-right (B_3,O) area of Stoddard’s plot, relative to the situation in vacuum. Comparison of free and potential surfaces is also provided for vacuum calculations.