Side‐chain control of β‐peptide secondary structures

Martinek, Tamás A.; Fülöp, Ferenc

doi:10.1046/j.1432-1033.2003.03756.x

Cited by 142 publications

(97 citation statements)

References 81 publications

(114 reference statements)

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“…Overall, interactions among the three β 3 V side chains bury 155 ± 13 Å 2 of hydrophobic surface area from water (24% of the surfaces of these side chains). These packing interactions may explain why these and other branched residues stabilize 14-helices 12,18,19 and suggest new avenues for the design of 14-helix bundles. 20,21 The remaining 14-helix face consists of residues that comprise the hDM2-binding epitope, namely, β 3 -homoleucine (β 3 L3), β 3 -homotryptophan (β 3 W6), and β 3 -homophenylalanine (β 3 F9).…”

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confidence: 94%

Solution Structure of a β-Peptide Ligand for hDM2

2005

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Recently, we described a β-peptide foldamer, β53-1 ( Figure 1A), that assembles into a 14-helix in aqueous solution, binds the oncoprotein hDM2 with submicromolar affinity, and inhibits the interaction of hDM2 with a peptide derived from the activation domain of p53 (p53AD). 1 The intact recognition epitope of β53-1, including a high degree of helical structure, is required for selective inhibition of the p53AD·hDM2 interaction. Here, we present the solution structure of β53-1 in methanol. The structure reveals details of a helixstabilizing salt bridge on one helical face, novel "wedge into cleft" packing along another, and how distortions in the β53-1 14-helix maximize presentation of the p53AD recognition epitope. These details deepen our understanding of how β 3 -peptides fold and how they can be designed to form higher order structures and bind macromolecules. 2,3 Two-dimensional NMR spectroscopy was performed using 5 mM β53-1 in CD 3 OH at 10°C. Previous circular dichroism and analytical ultracentrifugation experiments 1 and the NMR line widths observed herein are consistent with a monomeric, 14-helical structure for β53-1 under these conditions. The proton resonances of β53-1 were assigned unambiguously using TOCSY and natural abundance 1 H-13 C HSQC spectra. 4 ROESY experiments were then performed using mixing times of 200, 350, and 500 ms. 5 The observed series of NH-C α H ROEs confirmed the sequential assignment by providing a backbone "ROE walk". Three classes of medium-range ROEs characterize a 14-helical conformation: those between H N (i) and H β (i+2), H N (i) and H β (i+3), and H α (i) and H β (i+3). 6,7 All 20 potential medium-range interactions of this type were observed in the ROESY spectra of β53-1; in addition, 27 additional medium-range ROEs between side chains three positions apart were also observed. 4 The large number of medium-range ROEs observed by NMR provides clear evidence for a high level of 14-helix structure in β53-1; 449 ROEs quantified using a 350 ms mixing time were subsequently assigned and integrated using SPARKY. 8 Peak volumes were converted to 151 upper-limit distance constraints 4 and used to perform simulated annealing torsional dynamics on 100 random starting configurations of β53-1 using DYANA. 4,9 No constraint violations were reported among the resulting 20 lowest-energy structures, which are shown in Figure 1B.The ensemble of calculated structures of β53-1 ( Figure 1B) shows a 14-helix with an average backbone atom RMSD from the mean structure of 0.17 ± 0.07 Å. The backbone torsions of individual structures deviate little from the mean, even at the termini ( Figure 1C), illustrating the robustness of the β53-1 14-helix in methanol. .0 residues per turn for residues 1-6, with a slight unwinding to approximately 1.49 Å rise per residue and 3.3 residues per turn for residues 7-10. This unwinding appears to be unique to β53-1, as it was not observed in NMR structures of unrelated β 3 -peptides with and without side chain ion pairing. 6,7,10 Side chains are also well-de...

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confidence: 94%

Solution Structure of a β-Peptide Ligand for hDM2

2005

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“…When engineering a protein, it is worthwhile to look for principles that will make a design more effective. Detailed studies [84][85][86] have been carried out on the role of secondary structure preference in sequence design and the effect of amino acid substitution on helix formation. [87].…”

Section: Protein Engineeringmentioning

confidence: 99%

The thermodynamics and statistical mechanics of protein folding

Chapagain¹

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“…[1][2][3][4][5][6][7][8][9] Similarly to natural peptides, proteins, RNA and DNA, they fold into specific, well-defined 3D structures, with three properties of crucial importance: (i) hierarchical organization (primary, secondary and tertiary structure); (ii) cooperativity in folding; and (iii) sequence heterogenity. There are two major types of foldamers: (i) the aromatic foldamers with aromatic carbon atoms in the backbone, and (ii) aliphatic peptide-like foldamers with saturated carbon atoms between the Hbond pillar moieties.…”

Section: Foldamersmentioning

confidence: 99%

“…they have a tendency to fold into specific periodic compact structures. [1][2][3][4][5][6][7][8][9] Foldamers have the potential to achieve structural versatility similar to that of the natural proteins, and consequently they have numerous promising biological applications where the tailored 3D structure of the designed foldamers is crucial. Their most important applications are as: antibacterial or cell-penetrating amphiphiles, inhibitors of fat and cholesterol absorption, RNA-binding oligomers and antagonists of cancer-related proteins.…”

Section: Introduction and Aimsmentioning

confidence: 99%

“…The most thoroughly studied representatives of this field are the β-peptides, consisting of β-amino acids. [1][2][3][4][5][6][7][8][9] They populate a wide range of tunable secondary structures (numerous helices, sheet-forming strands and turn motifs) with a propensity to associate into tertiary structure-like motifs. 4 Novel secondary structural motifs can be gained (i) by the use of new non-natural amino acids and derivatives or (ii) through an understanding of the structure-promoting effect of the stereochemistry.…”

Section: Introduction and Aimsmentioning

confidence: 99%

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Tailoring β-peptide foldamers by backbone stereochemistry and side-chain topology

Mándity

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Side‐chain control of β‐peptide secondary structures

Cited by 142 publications

References 81 publications

Solution Structure of a β-Peptide Ligand for hDM2

Solution Structure of a β-Peptide Ligand for hDM2

The thermodynamics and statistical mechanics of protein folding

Tailoring β-peptide foldamers by backbone stereochemistry and side-chain topology

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