Conformational backbone dynamics of the cyclic decapeptide antamanide. Application of a new multiconformational search algorithm based on NMR data

Blackledge, Martin; Brüschweiler, Rafael; Griesinger, Christian; Schmidt, Joachim W.; Xu, Ping; Ernst, R. R.

doi:10.1021/bi00092a005

Cited by 96 publications

(98 citation statements)

References 48 publications

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“…To generate structures that better reflected the experimental data, a set of 51 absent distance restraints (ADRs) was added, in a manner similar to that described in ref. 18; each ADR involved proton pairs that showed no cross peak in the TROESY spectra. Only pairs for which both protons appeared in other ROE cross peaks were included.…”

Section: Methodsmentioning

confidence: 99%

NMR determination of the major solution conformation of a peptoid pentamer with chiral side chains

Armand

Kirshenbaum

Goldsmith

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

289

314

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Polymers of N-substituted glycines (''peptoids'') containing chiral centers at the ␣ position of their side chains can form stable structures in solution. We studied a prototypical peptoid, consisting of five para-substituted (S)-N-(1-phenylethyl)glycine residues, by NMR spectroscopy. Multiple configurational isomers were observed, but because of extensive signal overlap, only the major isomer containing all cis-amide bonds was examined in detail. The NMR data for this molecule, in conjunction with previous CD spectroscopic results, indicate that the major species in methanol is a right-handed helix with cis-amide bonds. The periodicity of the helix is three residues per turn, with a pitch of Ϸ6 Å. This conformation is similar to that anticipated by computational studies of a chiral peptoid octamer. The helical repeat orients the amide bond chromophores in a manner consistent with the intensity of the CD signal exhibited by this molecule. Many other chiral polypeptoids have similar CD spectra, suggesting that a whole family of peptoids containing chiral side chains is capable of adopting this secondary structure motif. Taken together, our experimental and theoretical studies of the structural properties of chiral peptoids lay the groundwork for the rational design of more complex polypeptoid molecules, with a variety of applications, ranging from nanostructures to nonviral gene delivery systems.Polymers of N-substituted glycines, termed peptoids, form a new class of biocompatible, synthetically accessible heteropolymers. Their sequence-specific, automated, and highly efficient synthesis has allowed the creation of combinatorial libraries of peptoid oligomers for drug discovery (1-3). By using recent improvements in the efficiency of the coupling chemistry, peptoids up to 50 residues in length have been synthesized. Among those, cationic peptoid 36-mers have been identified that bind DNA, protect the DNA from nuclease digestion, and facilitate gene transfection (4).We recently showed that many peptoids with chiral centers at the side chain ␣ position have strong CD signals, indicating the presence of a regularly repeating conformation, in both aqueous and organic solvents (5). This structure is remarkably stable, as demonstrated by both CD and differential scanning calorimetry (DSC) measurements (5). A model of this conformation was recently proposed based on the results of molecular mechanics and semi-empirical quantum mechanical calculations (6). Modeling predicted that peptoids containing (S)-N-(1-phenylethyl)glycine residues would form righthanded helices with a periodicity of approximately three residues per turn and cis-amide bonds, similar to the polyproline type I conformation. In this conformation, the backbone carbonyls are aligned along the long helical axis, providing an explanation for the intensity of the helical CD signal.Presented here is the structure determination by NMR spectroscopy of the major solution isomer of compound 1, a pentapeptoid containing five chiral side chains (Fig. 1A). ...

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Section: Methodsmentioning

confidence: 99%

NMR determination of the major solution conformation of a peptoid pentamer with chiral side chains

Armand

Kirshenbaum

Goldsmith

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

289

314

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“…Although local backbone fluctuations on the picosecond to nanosecond time scale have been the subject of detailed characterization using NMR (7,8) and molecular dynamics simulations (2), slower motions, in the submicrosecond to second range, remain poorly understood. Relaxation dispersion has been used to successfully identify sites of conformational exchange between states experiencing different chemical shifts in peptides (9) and proteins (10), but specific geometric motional models are often difficult to extract from these data. Slow time scales are, however, of particular interest because functionally important biological processes, including enzyme catalysis (11), signal transduction (12), ligand binding, and allosteric regulation (13), as well as collective motions involving groups of atoms or whole amino acids (14), are expected to occur in this time range.…”

mentioning

confidence: 99%

Identification of slow correlated motions in proteins using residual dipolar and hydrogen-bond scalar couplings

Bouvignies

Bernadó

Meier

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

225

311

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Despite their importance for biological activity, slower molecular motions beyond the nanosecond range remain poorly understood. We have assembled an unprecedented set of experimental NMR data, comprising up to 27 residual dipolar couplings per amino acid, to define the nature and amplitude of backbone motion in protein G using the Gaussian axial fluctuation model in three dimensions. Slower motions occur in the loops, and in the ␤-sheet, and are absent in other regions of the molecule, including the ␣-helix. In the ␤-sheet an alternating pattern of dynamics along the peptide sequence is found to form a long-range network of slow motion in the form of a standing wave extending across the ␤-sheet, resulting in maximal conformational sampling at the interaction site. The alternating nodes along the sequence match the alternation of strongly hydrophobic side chains buried in the protein core. Confirmation of the motion is provided through extensive crossvalidation and by independent hydrogen-bond scalar coupling analysis that shows this motion to be correlated. These observations strongly suggest that dynamical information can be transmitted across hydrogen bonds and have important implications for understanding collective motions and long-range information transfer in proteins.protein dynamics ͉ slow motions ͉ correlated M olecular dynamics, manifest in backbone and side-chain mobilities, play a crucial role in protein stability and function (1-4). The accurate characterization and understanding of protein motions thus adds an additional dimension to the structural information derived from genomics projects (5, 6). Although local backbone fluctuations on the picosecond to nanosecond time scale have been the subject of detailed characterization using NMR (7, 8) and molecular dynamics simulations (2), slower motions, in the submicrosecond to second range, remain poorly understood. Relaxation dispersion has been used to successfully identify sites of conformational exchange between states experiencing different chemical shifts in peptides (9) and proteins (10), but specific geometric motional models are often difficult to extract from these data. Slow time scales are, however, of particular interest because functionally important biological processes, including enzyme catalysis (11), signal transduction (12), ligand binding, and allosteric regulation (13), as well as collective motions involving groups of atoms or whole amino acids (14), are expected to occur in this time range. Residual dipolar couplings (RDCs) report on averages over longer time scales (up to the millisecond range) and therefore encode key information for understanding slower protein motions over a very broad time scale (15,16). Recent studies have exploited the orientational averaging properties of RDCs to characterize the amplitude and direction of motions of NH vectors (17)(18)(19) or to study local variations in position and dynamics of the amide proton (20,21). Despite this activity, key questions remain concerning the nature and amplitude of ...

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“…40 It is also interesting that T1 measurements and conformational search procedures suggest that local backbone dihedral angles accompany rapid hydrogen bond exchange. 41 …”

mentioning

confidence: 99%

The relationship between peptide plane rotation (PPR) and similar conformations

Parker

1999

J. Comput. Chem.

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Conformational backbone dynamics of the cyclic decapeptide antamanide. Application of a new multiconformational search algorithm based on NMR data

Cited by 96 publications

References 48 publications

NMR determination of the major solution conformation of a peptoid pentamer with chiral side chains

NMR determination of the major solution conformation of a peptoid pentamer with chiral side chains

Identification of slow correlated motions in proteins using residual dipolar and hydrogen-bond scalar couplings

The relationship between peptide plane rotation (PPR) and similar conformations

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