Crystal structure,conformation, and potential energy calculations the chemotactic peptide N- formyl-l-Met-l-Leu-l-Phe-OMe

The tripeptide N-formyl-L-Met-l -Leu-l -Phe-OMe (FMLP-OMe) crystallizes in the orthorhombic system, space group P 2₁2_l2₁, with the following unit-cell parameters: a = 21.727, b = 21.836, c = 5.133Å, Z = 4. The structure has been solved and refined to a final R of 0.068 for 1838 independent reflexions with I > 2σ(I). The peptide backbone is folded at the Leu residue (φ_L=?67.7,Ψ_L=?49.1°) without intramolecular hydrogen bonds. Considering each peptide plane, the Leu side-chain is oriented on the same side of that of the Phe residue and on the opposite side of that of the Met residue, respectively. The crystal conformation differs from all the other conformations proposed for FMLP-OMe and the anionic form of N-formyl-l -Met-l -Leu-l -Phe-OH (FMLP) in solution accounts for the amphiphilic character of the peptide, giving rise, through intermolecular hydrogen bonds, to a stacking of molecules which could be maintained in the aggregation states experimentally observed in solvents of low polarity. Intramolecular potential energy calculations have ben carried out in order to compare the energies of the various backbone conformers.     

Crystal structure of L-lysyl-L-glutamic acid dihydrate

L-Lysyl-L-glutamic acid dihydrate, C₁₁N₃O₅H₂₁·2H₂O, crystallizes in the monoclinic space group P2₁ with a = 12.474(2), b = 5.020(1), c = 13.157(2) Å, β= 114.69(1)° and Z = 2. The crystal structure was solved by direct methods and refined to an R value of 0.037 using full matrix least-squares method. The molecule exists as a double zwitterion with both the amino and carboxyl groups ionised. The peptide has a folded conformation with its Lys residue trans and Glu residue gauche^?gauche⁺. The side chains of the Lys and Glu residues correspond to all trans and folded (g^?g^?g^?) conformations respectively. The terminal carboxyl group forms hydrogen bonds with the ξ-amino group of the lysine side chain. The head-to-tail interaction often seen in peptide crystals is absent in the present structure. In the extended crystal structure water molecules form channels along the b direction and are enclosed within helically arranged hydrogen bonds formed by the lysine side chain and the peptide backbone.     

Conformational comparison of µ‐selective endomorphin‐2 with its C‐terminal free acid in DMSO solution,by 1H NMR spectroscopy and molecular modeling calculation

Abstract: In order to make clear the structural role of the C‐terminal amide group of endomorphin‐2 (EM2, H‐Tyr‐Pro‐Phe‐Phe‐NH₂), an endogenous µ‐receptor ligand, in the biological function, the solution conformations of endomorphin‐2 and its C‐terminal free acid (EM2OH, H‐Tyr‐Pro‐Phe‐Phe‐OH), studied using two‐dimensional ¹H NMR measurements and molecular modeling calculations, were compared. Both peptides were in equilibrium between the cis and trans isomers around the Tyr‐Pro ω bond in a population ratio of ≈ 1 : 2. The lack of significant temperature and concentration dependence of NH protons suggested that the NMR spectra reflected the conformational features of the respective molecules themselves. Fifty possible 3D structures for the each isomer were generated by the dynamical simulated annealing method under the proton?proton distance constraints derived from the ROE cross‐peaks. These energy‐minimized conformers, which were all in the φ torsion angles estimated from J_NHCαH coupling constants within ± 30°, were then classified in groups one or two according to the folding backbone structures. All trans and cis EM2 conformers adopt an open conformation in which their extended backbone structures are twisted at the Pro²–Phe³ moiety. In contrast, the trans and cis conformers of EM2OH show conformational variation between the ‘bow’‐shaped extended and folded backbone structures, although the cis conformers of its zwitterionic form are refined into the folded structure of the close disposition of C‐ and N‐terminal groups. These results indicate clearly that the substitution of carboxyl group for C‐terminal amide group makes the peptide flexible. The conformational requirement for µ‐receptor activation has been discussed based on the active form proposed for endomorphin‐1 and by comparing conformational features of EM2 and EM2OH.     

Design of peptides with αβ-dehydro residues: Synthesis,crystal structure and molecular conformation of N-Boc-L-Ile-ΔPhe-L-Trp-OCH3

The dehydro-peptide Boc-L-Ile-ΔPhe-L-Trp-OCH₃ was synthesized by the azlactone method in the solution phase. The peptide was crystallized from methanol in an orthorhombic space group P2₁2₁2₁ with a = 10.777(2), b= 11.224(2), c= 26.627(10) Å. The structure was determined by direct methods and refined to an R value of 0.069 for 3093 observed reflections [l≥ 2σ(l)].The peptide failed to adopt a folded conformation with backbone torsion angles: φ₁, = 90.8(8)°, ψ₁= -151.6(6)°, φ₂= 89.0(8)°, ψ₂= 15.9(9)°, φ₃= 165.7(7)°, ψ^T₃= -166.0(7)°. A general rule derived from earlier studies indicates that a three-peptide unit sequence with a ΔPhe at the (i+ 2) position adopts a β-turn II conformation. Because the branched β-carbon residues such as valine and isoleucine have strong conformational preferences, they combine with the ΔPhe residue differently to generate a unique set of conformations in such peptides. The presence of β-branched residues simultaneously at both (i+ 1) and (i+ 3) positions induces unfolded conformations in tetrapeptides, but a β-branched residue substituted only at (i+ 3) positron can not prevent the formation of a folded β-turn II conformation. On the other hand, the present structure shows that a β-branched residue substituted at the (i+ 1) position prevents the formation of a β-turn II conformation. These observations indicate that a β-branched residue at the (i+ 1) position prevents a folded conformation whereas it cannot generate the same degree of effect from the (i+ 3) position. This may be because of the trans disposition of the planar ΔPhe side-chain with respect to the C=O group in the residue. The molecules are packed in an anti-parallel manner to generate N₂-H₂…O₂ (-x,y-1/2, -z+ 3/2) and N^ε1₃-H^ε1₃…O₁(-x,y -1/2, -z+ 3/2) hydrogen bonds.     

Crystal and molecular structure of two geometrically restricted chemotactic tripeptides,analogues of formyl-methionine-leucine-phenylalanine*

The crystal structures of HCO-Met-Leu-Phe-OC(CH₃)₃, (CH₂₅H₃₉N₃O⁵S), fMLP-OtBu, and HCO-Metψ[CSNH]-Leu-Phe-OCH₃, (C₃₃H₃₃N₃O₄S₂), fM^SLP-OMe, have been determined by single crystal X-ray diffraction, and their conformational properties investigated by molecular mechanics energy calculations. Crystals of fMLP-OtBu are monoclinic, space group P2₁, a = 12.027(4), b = 9.492(3), c = 12.660(4) Å, β= 101.99(3)°, Z = 2; those of fM^SLP-OMe are orthorhombic, space group P2₁2₁2₁, a = 7.130(1), b = 12.097(2), c = 31.060(5) Å, Z = 4. The first compounds fMLP-OtBu is the t-butyl ester of the tripeptide fMLP that represents one of the most potent compounds in inducing the lysozyme release from human neutrophils that reflects the chemotactic activity. From the crystal structure, it is shown that the orientation of the phenylalanine side chain is largely affected by the presence of the bulky group. fM^SLP-OMe was shown to be inactive after thionation of the methionine residue in the original tripeptide. Nevertheless, the crystal structure does not reveal any influence of the presence of the thionated peptidic bond on the backbone conformation. The X-ray results have been used to generate parameters for empirical energy calculations. Subsequently, a strategy based on random generation of conformations followed by energy-minimization was applied to investigate the conformational space of thiopeptides, in comparison with normal peptides. From molecular free energy calculations, it is shown that the main influence of the introduction of a thioamide bond on the molecular structure is to prevent the existence of C⁷_eqconformations involving the thiomethionine residue. Consequently, a larger number of conformers are found to form intramolecular hydrogen bonds involving the formyl group, reducing its availability to interact with the receptor. For the first time, the theoretical prediction of the existence of C⁷_eq conformations for fMLP is made. The resulting conformers are compared to previously active structures of these chemotactic agents.     

N-METHYL PEPTIDES: III. Solution Conformational Study and Crystal Structure of N>-Pivaloyl-L-Prolyl-N-Methyl-N‘-Isopropyl-L-Alaninamide*

The study of tBuCO-l -Pro-Me-l -Ala-NHiPr (1) by i.r. and n.m.r. spectroscopies has indicated that the middle amide group accommodates preferentially the cis arrangement in inert (CCl₄) and aprotic (DMSO) solvents. Cis conformers are folded by a strong intramolecular hydrogen bond involving both terminal CO and NH groups whereas the minor trans conformers accommodate an open conformation. The cis folded form is retained in the solid state and its crystal structure was fully characterized by X-ray diffraction.     

CONFORMATIONAL CALCULATIONS ON GASTRIN C-TERMINAL TETRAPEPTIDE

Energy optimizations were performed on some typical conformations of the gastrin C-terminal peptide amide NAc-Trp-Met-Asp-Phe-NH₂. Two families of lowest energy conformations were found corresponding to: (a) α-helical structures; (b) conformations having β-structure at the level of Trp residue, and C₇-structure at the level of Asp residue. The two aromatic rings were folded on the peptide backbone and ca. 5 Å distant from each other (centre to centre). The last family, favoured by energy and population probability, can better account for conformational experimental results and biological activity observations.     

Comparison of conformational properties of linear and cyclic δ selective opioid ligands DTLET (Tyr-D-Thr-Gly-Phe-Leu-Thr) and DPLPE (Tyr-c[D-Pen-Gly-Phe-Pen]) by 1H n.m.r. spectroscopy

The preferential conformations of the δ selective opioid peptides DPLPE (Tyr-c[D-Pen-Gly-Phe-Pen]) and DTLET (Tyr-D-Thr-Gly-Phe-Leu-Thr) were studied by 400 MHz ¹H n.m.r. spectroscopy in DMSO-d₆ solution. In neutral conditions, the weak NH temperature coefficients of the C-terminal residue (Pen⁵ or Thr⁶), associated with interproton NH-NH and α-NH NOE's (ROESY experiments), indicated large analogies between the backbone folding tendency of both the linear and cyclic peptides. Various γ and/or β turns may account for these experimental data. A similar orientation of the N-terminal tyrosine related to the folded backbones is observed for the two agonists, with a probable γ turn around the amino acid in position 2. Finally, a short distance, about 10 Å, between Tyr and Phe side chains and identical structural roles for threonyl and penicillamino residues are proposed for both peptides. These results suggest the occurrence of similar conformers in solution for the constrained peptide DPLPE and the flexible hexapeptide DTLET. Therefore, it may be hypothesized that the enhanced δ selectivity of DPLPE is related to a very large conformational expense of energy needed to interact with the μ opioid receptor, a feature not encountered in the case of DTLET. These findings might allow peptides to be designed retaining a high affinity for δ opioid receptors associated with a very low cross-reactivity with μ binding sites.     

Comparative conformational analyses of μ-selective dermorphin and §-selective deltorphin-II in aqueous solution by 1H-NMR spectroscopy

Two-dimensional ¹H-NMR methods have been used to obtain complete proton resonance assignments and possible solution conformations of dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH₂) and deltorphin-II (H-Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH₂), naturally occurring μ and §-selective opioids, respectively, in order to examine the conformational characteristics that are closely related to the selectivities towards μ/§ opioid receptors. With the use of the proton-proton distances derived from ROESY measurements in aqueous solution, 50 possible 3D structures are generated by means of distance geometry calculations. The conformers which satisfy the distance constraints and the torsion angles estimated from J_NHCxH vicinal coupling constants within the allowable range are then subjected to molecular dynamics simulations for 10 ps after equilibration. Although dermorphin and deltorphin-II are both in equilibrium among many flexible conformers, some conformational differences are observed between these peptides: many conformers of dermorphin show a structure rounded at the N-terminal Tyr-D-Ala-Phe-Gly-Tyr and C-terminal Gly-Tyr-Pro-Ser-NH₂ moieties, which are almost at right angles to each other, while those of deltorphin-II are characterized by a ‘hook’ -shaped backbone structure in which the nearly extended conformation of the Val-Val-Gly-NH₂ sequence is located under the folded conformation of the N-terminal Tyr-D-Ala-Phe-Glu sequence. The possible relationship between these conformational characteristics and the μ/§-opioid receptor selectivities is discussed.     

Solution conformations of the peptide backbone for DPDPE and its β-MePhe4-substituted analogs

The solution structures of DPDPE, a conformationally restricted pentapeptide with the sequence H-Tyr¹-d -Pen²-Gly³-Phe⁴-d -Pen⁵-OH, and its four β-MePhe⁴-substituted analogs were examined by a combined approach including the NMR measurements in DMSO and water as well as independent energy calculations. It was concluded that several low energy conformers of DPDPE backbone satisfy the NMR data obtained in this study as well as in previous studies by other authors. These possible solution conformers of DPDPE in both DMSO and water share virtually the same type of cyclic backbone structure, with the Gly³ residue in a conformation close to a γ-turn, and the Phe⁴ residue in a conformation close to α-helical torsion angles. They differ in the space arrangements of the flexible Tyr¹ moiety. The solution structures of the β-MePhe⁴-substituted analogs of DPDPE are interesting. For analogs with an S-configuration at the C^α atom in the Phe⁴ residue, the cyclic backbone conformations resemble those of DPDPE itself, whereas for analogs with an R-configuration at the C^α atom, the backbone conformation is somewhat different. This observation is in line with the high biological potencies and selectivities displayed by the former compounds but not by the latter ones. It was noted also that as far as the peptide backbone conformers are concerned, some of the possible DPDPE conformers in water are similar to the previously suggested model for the δ-receptor-bound conformation of DPDPE, becoming virtually identical to this conformation by rotating the side chains of the Tyr¹ and the Phe⁴ residues.     

Crystal and molecular structure of cyclo(L-prolyl-glycyl)3

The crystal structure of cyclo(L-Pro-Gly)₃ was solved using X-ray crystallographic techniques. The backbone of the peptide is asymmetric and is made up of five trans peptide units and one cis peptide. There is a hydrogen bonded water bridge that links the carbonyl oxygens, O1 and O4. The molecules exist as dimers in the crystal lattice. The two molecules of the dimer are related by crystallographic twofold symmetry and are linked by two N-H O hydrogen bonds. The crystals are trigonal, space group P3₂12 with a = 11.379(3), c = 32.93(1) and z = 6. The structure was solved by multisolution methods and refined by least squares technique to an R of 0.083.     

Conformations of dehydrophenylalanine containing peptides Nuclear Overhauser effect study of two acyclic tetrapeptides

Two isomeric, acyclic tetrapeptides containing a Z-dehydrophenylalanine residue (Δ^z-Phe) at position 2 or 3, Boc-Leu-Ala-Δ^z-Phe-Leu-OMe (1) and Boc-Leu-Δ^z-Phe-Ala-Leu-OMe (2), have been synthesized and their solution conformations investigated by 270MHz ¹H n.m.r. spectroscopy. In peptide 1 the Leu(4) NH group appears to be partially shielded from solvent, while in peptide 2 both Ala(3) and Leu(4) NH groups show limited solvent accessibility. Extensive difference nuclear Overhauser effect (n.O.e.) studies establish the occurrence of several diagnostic inter-residue n.O.e.s (Cα_jH ? N_i+1H and N_iH ? N_i+1H) between backbone protons. The simultaneous observation of “mutually exclusive” n.O.e.s suggests the presence of multiple solution conformations for both peptides. In peptide 1 the n.O.e. data are consistent with a dynamic equilibrium between an -Ala-Δ^z-Phe- Type II β-turn structure and a second species with Δ^z-Phe adopting a partially extended conformation with Ψ values of ± 100° to ± 150°. In peptide 2 the results are compatible with an equilibrium between a highly folded consecutive β-turn structure for the -Leu-Δ^z-Phe-Ala- segment and an almost completely extended conformation.     

Crystal and molecular structure of Boc-Phe-Val-OMe; comparison of the peptide conformation with its dehydro analogue

The crystal structure of the peptide Boc-Phe-Val-OMe determined by X-ray diffraction methods is reported in this paper. The crystals grown from aqueous methanol are orthorhombic, space group P 2₁2₁ 2₁, a= 11.843(2), b= 21.493(4), c= 26.676(4) A and V= 6790 ų. Data were collected on a CAD4 diffractometer using MoK_α radiation (λ= 0.7107 Å) up to Bragg angle θ=26°. The structure was solved by direct methods and refined by a least-squares procedure to an R value of 6.8% for 3288 observed reflections. There are three crystal-lographically independent peptide molecules in the asymmetric unit. All the three molecules exhibit extended conformation. The sidechain of the Val² residue shows two different conformations. The conformation of the peptide Boc-Phe-Val-OMe is compared with the conformation of Ac-ΔPhe-Val-OH. It is observed that while Boc-Phe-Val-OMe exhibits an extended conformation, Ac-ΔPhe-Val-OH shows a folded conformation. The results of this comparison highlight the conformation constraining property of the ΔPhe residue. Interestingly, even though Boc-Phe-Val-OMe and Ac-ΔPhe-Val-OH are conformation ally different, they exhibit similar packing patterns in the solid state. © Munksgaard 1995.     

Stereochemical analysis of the antigenic tip of the V3 loop peptide of HIV-1 gp120

A novel multiple turn conformation has been observed for a segment GPGRAFY in the crystal structure of a complex of HIV-1 gp120 V3 loop peptide with the Fab fragment of a neutralizing antibody [Ghiara et al. (1994) Science 264 , 82–85]. A structural motif has been defined for the peptide segment, employing idealized backbone conformations characterized by ranges of virtual C^α torsion angles and bond angles. A search of 122 high-resolution protein crystal structures has permitted identification of 24 examples of similar structural motifs. Two major conformational families have been identified, which differ primarily in the conformation at residue 3. The observed conformation at residue 3 in family 1 is left-handed helical (α_L) and that in family 2 is right-handed helical (α_R). Of the 10 examples in family 1, 9 examples have Gly residues at position 3. Of the 12 examples in family 2, 7 examples have Asn/Asp at position 3. Computer modeling of the V3 loop tip sequence using the two backbone conformational families as starting points leads to minimum-energy conformations in which antigenically important side-chains occupy similar spatial arrangements. This stereo-chemical analysis of the V3 loop tip sequence suggests a rational basis for the design of synthetic analog peptides for use as viral antagonists or synthetic antigens. © Munksgaard 1995.     

Synthesis and solution conformation of c(D-Trp-D-Cys(SO3-Na+)-Pro-D-Val-Leu), a potent endothelin-A receptor antagonist

The endothelin family of polypeptides are known to exert potent physiological effects which include cardiovascular regulation. The solution conformation and dynamics of c(D-Trp-D-Cys(SO₃-Na⁺)-Pro-D-Val-Leu), a potent endothelin-A receptor-selective antagonist, were characterized in aqueous solution by NMR spectroscopy and molecular modeling. NMR-derived conformational constraints were combined with computer-assisted molecular modeling using distance geometry calculations and energy minimization. The pentapeptide backbone is shown to adopt a single conformation in solution comprising a type II β-turn and an inverse γ-turn, with each residue in the trans conformation. Molecular dynamics were explored using relaxation measurements and low-temperature studies, and indicate that the peptide backbone is highly constrained with little conformational mobility present.     

Crystal structure of tert.-butyloxycarbonyl-L-prolyl-D-alanyl-D-alanyl-N-methylamide Dimeric β-sheet formation

The crystal structure of the tripeptide t-Boc-L-Pro-D-Ala-D-Ala-NHCH₃, monohydrate, (C₁₇H₃₀N₄O₅·H₂O, molecular weight = 404.44) has been determined by single crystal X-ray diffraction. The crystals are mono-clinic, space group P2₁, a = 9.2585(4), b = 9.3541(5). c = 12.4529(4) Å, β= 96.449(3)°, Z = 2. The peptide units are in the trans and the tBoc-Pro bond in the cis orientation. The first and third peptide units show significant deviations from planarity (Δω=5.2° and Δω=3.7°, respectively). The backbone torsion angles are: φ¹, = -60°, ψ_1/= 143.3°, ω₁= -174.8°, φ₂= 148.4°, ψ₂= -143.1°, ω₂= -179.7°, φ₃= 151.4°, ψ₃= -151.9°, ω₃= -176.3°. The pyrrolidine ring of the proline residue adopts the C₂— C^γ conformation. The molecular packing gives rise to an antiparallel β-sheet structure formed of dimeric repeating units of the peptide. The surface of the dimeric β-sheet is hydrophobic. Water molecules are found systematically at the edges of the sheets interacting with the urethane oxygen and terminal amino groups. Surface catalysis of an L-Ala to D-Ala epimerization process by water molecules adsorbed on to an incipient β-sheet is suggested as a mechanism whereby crystals of the title peptide were obtained from a solution of tBoc-Pro-D-Ala-Ala-NHCH₃.     

Protected 1–3 segment of the peptaibol antibiotics alamethicin and hypelcin.

A study of the modes of folding and self-association of Z-Aib-l -Pro-Aib-OMe (the protected 1–3 segment of the peptaibol antibiotics alamethicin and hypelcin) in the solid state was performed using i.r. absorption and X-ray diffraction. The stereochemically constrained tripeptide molecules adopt a 4 ± 1 intramolecularly H-bonded form (β-turn), where the single intramolecular H-bond is found between the peptide N-H group of the Aib³ residue and the urethane C = O group of the N-blocking benzyloxycarbonyl moiety. This folded structure is stabilized by an intermolecular H-bond between the urethane N-H group of the Aib¹ residue and the peptide C = O group of the Pro² residue of a symmetry related molecule. According to the i.r. absorption data, in CH₂Cl₂ and TMP solutions the same intramolecularly H-bonded form occurs as that found in solid state. Compared to the situation in the solid state, in CH₂Cl₂ and TMP solvation of the urethane N-H group replaces self-association (through the same N-H group). The results are also discussed in relation to those obtained for other protected -Aib-X-Aib-(X = Aib, l -Ala, l -Val) tripeptide segments of peptaibol antibiotics.     

Stabilization of β-turn conformations in enkephalins

Stereochemical constraints have been introduced into the enkephalin backbone by substituting α-aminoisobutyryl (Aib) residues at positions 2 and 3, instead of Gly. ¹H n.m.r. studies of Tyr-Aib-Gly-Phe-Met-NH₂, Tyr-Aib-Aib-Phe-Met-NH₂ and Tyr-Gly-Aib-Phe-Met-NH₂ demonstrate the occurrence of folded, intramolecularly hydrogen bonded structures in organic solvents. Similar conformations are also favoured in the corresponding t-butyloxycarbonyl protected tetrapeptides, which lack the Tyr residue. A β-turn centred at positions 2 and 3 is proposed for the Aib²-Gly³analog. In the Gly²-Aib³analog, the β-turn has Aib³-Phe⁴as the corner residues. The Aib²-Aib³analog adopts a consecutive β-turn or 3₁₀ helical conformation. High in vivo biological activity is observed for the Aib²and Aib²-Aib³analogs, while the Aib³peptide is significantly less active.     

Conformational investigation of α,β-dehydropeptides VII*. Conformation of Ac-Pro-ΔAla-NHCH3 and Ac-Pro-(E)-ΔAbu-NHCH3: comparison with (Z)-substituted α,β-dehydropeptides†

The crystal structure and solution conformation of Ac-Pro-ΔAla-NHCH₃ and the solution conformation of Ac-Pro-(E)-ΔAbu-NHCH₃ were investigated by X-ray diffraction method and NMR, FTIR and CD spectroscopies. Ac-Pro-ΔAla-NHCH, adopts an extended-coil conformation in the crystalline state, with all-trans peptide bonds and the ΔAla residue being in a C₅ form, φ₁=– 71.4(4), ψ₁=– 16.8(4), φ₂=– 178.4(3) and ψ₂= 172.4(3)°. In inert solvents the peptide also assumes the C₅ conformation, but a γ-turn on the Pro residue cannot be ruled out. In these solvents Ac-Pro-(E)- ΔAbu-NHCH₃ accommodates a βII-turn, but a minor conformer with a nearly planar disposition of the CO—NH and C=C bonds (φ₂～0°) is also present. Previous spectroscopic studies of the (Z)-substituted dehydropeptides Ac-Pro-(Z)- ΔAbu-NHCH, and Ac-Pro-ΔVal-NHCH₃ reveal that both peptides prefer a βII-turn in solution. Comparison of conformations in the family of four Ac-Pro-ΔXaa-NHCH₃ peptides let us formulate the following order of their tendency to adopt a β-turn in solution: (Z)- ΔAbu > (E)- δAbu > ΔVal; ΔAla does not. None of the folded structures formed by the four compounds is stable in strongly solvating media. © Munksgaard 1996.     

Conformational study of a peptide epitope shows large preferences for β-turn conformations

The conformational preferences of the 7-residue peptide Glu-Val-Val-Pro-His-Lys-Lys was investigated using a global search algorithm, namely the Electrostatically Driven Monte Carlo (EDMC) method, and the ECEPP/2 potential energy function. This particular sequence corresponds to the N-terminal portion of a 19-residue peptide antigen whose three dimensional structure, when complexed to a cognate antibody, was reported recently. As a result of this study a series of low-energy conformations were identified showing a common folding pattern with residues Val-3, Pro-4, His-5 and Lys-6 forming a β turn. A comparison of the computed conformations with the one determined by X-ray crystallography in the antibody-antigen complex reveals marked similarities. In most of the cases rms deviations smaller than 1.1 Å were found for the backbone atoms of the four residues forming the turn. These results suggest that the recognition process is accomplished in this case through the interaction of the antibody with relatively stable conformers of the antigenic peptide.