Determination of cyclopeptide conformations in solution using NMR data and conformational energy calculations

Shenderovich, Mark D.; Nikiforovich, Gregory V.; Saulitis, Juris; Chipens, G. I.

doi:10.1016/0301-4622(88)80022-x

Cited by 14 publications

(18 citation statements)

References 29 publications

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“…Such a situation involving two conformations in the same region has been described previously for other cyclopeptides. The human endothelin‐2 [67] adopts in its 5–8 region a βI turn (A form) or a structure compatible with no common secondary structure (B form). A cyclic analogue of substance P C‐terminal hexapeptide (CSP6) [68] forms, in the 1–4 region, a βII or βIII 1–4 turn conformation, or, in a minority of structures, a γ 1–3 turn.…”

Section: Discussionmentioning

confidence: 99%

NMR structure of active and inactive forms of the sterol‐dependent antifungal antibiotic bacillomycin L

Volpon

Besson

Lancelin

1999

European Journal of Biochemistry

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The antifungal antibiotic lipopeptide bacillomycin L [cyclo-(l-Asp1-d-Tyr2-d-Asn3-l-Ser4-l-Gln5-d-Ser6-lThr7-b-amino fatty acid)] from Bacillus subtilis belongs to the iturinic family of antifungal agents and acts with a strict sterol-phospholipid dependence on biomembranes. This antibiotic has been analysed using solution NMR spectroscopy in its native active form and its inactive (l-Asp1, d-Tyr2) di-O-methylated form. The structures were calculated under NMR-derived restraints using molecular-dynamic simulated-annealing protocols starting from a random array of atoms. The structure of the native antibiotic is spread over different conformers in which two families are recognized. It was found that most structures have dihedral f and c angles defining a type-II H b-turn including amino acids 5±8, in certain cases stabilized by a 8H N -5CO hydrogen bond, whereas a minority of structures adopt an inverse g-turn including amino acids 6±8, stabilized in all cases by an 8H N -6CO hydrogen bond. The di-O-methylation of l-Asp1 and d-Tyr2, an amino acid strictly conserved within the iturinic group of antibiotics, does not induce major differences in the NMR spectra and in the NMR structures. The results are discussed in relation to the specific loss of interaction with sterols when the native antifungal bacillomycin L is methylated on the conserved d-Tyr2 position.Keywords: antibiotics; antifungals; bacillomycin L; NMR.Among the antifungal antibiotic substances, there is a specific family of molecules that acts on the biomembrane of infectious agents with an established sterol dependency. This family comprises very different molecules including the polyene macrolides as the widely used nystatins or amphotericins in pharmacotherapy (for reviews see [1,2]). The antifungal activity is believed to rely on a better interaction with ergosterol, which is more abundant in the lipid composition of fungal membranes, than cholesterol present in other organisms. However, the fine nature of the molecular interaction and the origin of this selectivity at atomic resolution remain unknown [3±6]. Lipidic cyclopeptides (lipopeptides) isolated from cultures of bacterial strains of Bacillus subtilis also exhibit such a general property. Their peptidic nature potentially makes them more adapted for a drug-design approach or a combinatorial-chemistry search for more active or more suitable molecules. These peptides include iturins [7±9], bacillomycins [10±14] and mycosubtilin [15]. All antibiotics of the iturinic group (Fig. 1) are characterized by an invariant lddlldl amino acid sequence alternation with a conserved tyrosine residue at position 2, and variable hydrophobic tails [16] with the R absolute configuration at C 3 [17] linked into the cyclic peptide through a b-peptide bond. The molecular structure of two members, mycosubtilin [18] and iturin A [19,20], have already been studied mainly using solution NMR spectroscopy.All these lipopeptides are also haemolytic [21±23], very potent against fungi [24] and different yeasts [25±27], but...

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Section: Discussionmentioning

confidence: 99%

NMR structure of active and inactive forms of the sterol‐dependent antifungal antibiotic bacillomycin L

Volpon

Besson

Lancelin

1999

European Journal of Biochemistry

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“…1. The local interproton distances d, , in peptides and proteins are distributed in the range 2.0 to 4.8A, the minimum of the distribution being at 3.0-4.0A (19). In the NH-NH part of the ROESY spectrum (Fig.…”

Section: Comparison Of Some 'H-nmr Characteristics Measured In Dmso Smentioning

confidence: 93%

“…19). Using the experience of our previous studies under similar experimental conditions (19,20), we tentatively supposed that the three NOE grades correspond to three intersecting regions of interproton distances: d 2 3.0& 2.5A < d < 4.0& and d < 3.0& respectively. Third, the NOE intensities were divided into three grades: 0 -effects not observed in the ROESY spectrum (Fig.…”

Section: Conformations Of the Cyclic Moietymentioning

confidence: 99%

“…1, part B)is characteristic of the trans peptide bond (4,19,26), while the NOF; between the Cys6 and Sar7C"H resonances of the minor isomer (the cross-peak indicated as mC6-mSc' inFig. NOE connections of the c" H resonances of the Cys6 residue prove the cis-trans isomerization of the Cys6-Sar7 peptide bond.…”

mentioning

confidence: 98%

“…A simple scheme of calculations has recently been proposed for the determination of the favorable solution conformations of conformationally restrained peptides (19). Distance geometry algorithms (14, 15), restrained molecular dynamics (16, 17), and conformational energy minimization (4, 18) are widely used for this purpose in combination with experimental constraints derived from NMR parameters.…”

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confidence: 99%

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Conformational analysis of [Cpp¹, Sar⁷, Arg⁸] vasopressin by ¹H‐NMR spectroscopy and molecular mechanics calculations

Shenderovich

Kasprzykowski

Liwo

et al. 1991

International Journal of Peptide and Protein Research

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A combined 'H-NMR and molecular mechanics study of [Cpp', Sar7]AVP was performed in order to select the most probable conformations in DMSO solutions. The NMR constraints obtained were employed in the selection of starting conformations of the cyclic moiety of the analog. In particular, the diminished accessibility of the Asn' NH proton to solvent and the close contact between Cpp' and Cys6 C'H protons suggests a 8-turn conformation at the Phe'-Gln4 residues. Energy minimization was carried out both in the ECEPP/2 (rigid-valence geometry) and in the AMBER (flexible-valence geometry) force fields. Comparison of the experimental and calculated values of NMR characteristics has revealed that conformations containing type I, 11, and 111 P-turns at the Phe3-Gln4 residues are in reasonable agreement with the experimental data, with a dynamic equilibrium between the 81 (PIII) and p11 type structures of the cyclic part being the most probable. All of these conformations prefer the negative chirality of the disulfide bridge (xz 2 -90").Five representative conformations were chosen for the acyclic tail: one with a PI, one with a bII'-turn at the Sar7-Arg' residues, two extended-type conformations, and a conformation with a ;-turn at Sar7. Because only high-energy extended conformations were in agreement with NMR data, it was concluded that the acyclic tail has considerable conformational flexibility in solution. The conformations obtained are discussed in terms of the structure-function relationship of the neurohypophyseal hormone analogs.

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Efficiency of simulated annealing for peptides with increasing geometrical restrictions

Baysal

Meirovitch

1999

J. Comput. Chem.

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Determination of cyclopeptide conformations in solution using NMR data and conformational energy calculations

Cited by 14 publications

References 29 publications

NMR structure of active and inactive forms of the sterol‐dependent antifungal antibiotic bacillomycin L

NMR structure of active and inactive forms of the sterol‐dependent antifungal antibiotic bacillomycin L

Conformational analysis of [Cpp¹, Sar⁷, Arg⁸] vasopressin by ¹H‐NMR spectroscopy and molecular mechanics calculations

Efficiency of simulated annealing for peptides with increasing geometrical restrictions

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Determination of cyclopeptide conformations in solution using NMR data and conformational energy calculations

Cited by 14 publications

References 29 publications

NMR structure of active and inactive forms of the sterol‐dependent antifungal antibiotic bacillomycin L

NMR structure of active and inactive forms of the sterol‐dependent antifungal antibiotic bacillomycin L

Conformational analysis of [Cpp1, Sar7, Arg8] vasopressin by 1H‐NMR spectroscopy and molecular mechanics calculations

Efficiency of simulated annealing for peptides with increasing geometrical restrictions

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Conformational analysis of [Cpp¹, Sar⁷, Arg⁸] vasopressin by ¹H‐NMR spectroscopy and molecular mechanics calculations