Natural polypeptide scaffolds: β‐sheets, β‐turns, and β‐hairpins

Rotondi, Kenneth S.; Gierasch, Lila M.

doi:10.1002/bip.20390

Cited by 41 publications

(37 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Compound 1 has reduced conformational freedom relative to 4 and 6. The and dihedral angle equivalents in 4 are restricted by allylic strain (A 1,2 and A 1,3 ) relative to 6 (39). Compound 5, designed to replace the i ϩ 1 and i ϩ 2 residues of a type II ␤-turn (25), was expected to introduce a Pin WW twist preference mismatch.…”

Section: Resultsmentioning

confidence: 99%

“…beta-sheet nucleator ͉ kinetic assessment of turn mimics ͉ Pin WW domain ͉ protein folding L oops and turns enable the formation of compact protein structures (1,2). Numerous reports analyzing structural databases, studying peptide model systems, and perturbing known protein structures have revealed many examples where ␤-sheet folding is nucleated or envisioned to be nucleated by reverse turn formation (3)(4)(5)(6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Evaluating β-turn mimics as β-sheet folding nucleators

Fuller

Liu

et al. 2009

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

100

View full text Add to dashboard Cite

␤-Turns are common conformations that enable proteins to adopt globular structures, and their formation is often rate limiting for folding. ␤-Turn mimics, molecules that replace the i ؉ 1 and i ؉ 2 amino acid residues of a ␤-turn, are envisioned to act as folding nucleators by preorganizing the pendant polypeptide chains, thereby lowering the activation barrier for ␤-sheet formation. However, the crucial kinetic experiments to demonstrate that ␤-turn mimics can act as strong nucleators in the context of a cooperatively folding protein have not been reported. We have incorporated 6 ␤-turn mimics simulating varied ␤-turn types in place of 2 residues in an engineered ␤-turn 1 or ␤-bulge turn 1 of the Pin 1 WW domain, a three-stranded ␤-sheet protein. We present 2 lines of kinetic evidence that the inclusion of ␤-turn mimics alters ␤-sheet folding rates, enabling us to classify ␤-turn mimics into 3 categories: those that are weak nucleators but permit Pin WW folding, native-like nucleators, and strong nucleators. Strong nucleators accelerate folding relative to WW domains incorporating all ␣-amino acid sequences. A solution NMR structure reveals that the native Pin WW ␤-sheet structure is retained upon incorporating a strong E-olefin nucleator. These ␤-turn mimics can now be used to interrogate protein folding transition state structures and the 2 kinetic analyses presented can be used to assess the nucleation capacity of other ␤-turn mimics.beta-sheet nucleator ͉ kinetic assessment of turn mimics ͉ Pin WW domain ͉ protein folding

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Evaluating β-turn mimics as β-sheet folding nucleators

Fuller

Liu

et al. 2009

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

100

View full text Add to dashboard Cite

show abstract

“…[1] More recently, peptides have become very attractive as scaffolds in the development of smart biomaterials. [2,3] Engineering new intramolecular disulfide bonds in peptide structures is a simple strategy to stabilize them. [4] In fact, some natural antimicrobial peptides consist of b-hairpin structures stabilized by several disulfide bonds.…”

Section: Introductionmentioning

confidence: 99%

Context‐Dependence of the Contribution of Disulfide Bonds to β‐Hairpin Stability

Santiveri

León

Rico

et al. 2007

Chemistry A European J

View full text Add to dashboard Cite

Incorporation of disulfide bonds to stabilize protein and peptide structures is not always a successful strategy. To advance current knowledge on the contribution of disulfide bonds to beta-hairpin stability, a previously reported beta-hairpin-forming peptide was taken as a template to design a series of Cys-containing peptides. The conformational behavior of these peptides in their oxidized, disulfide-cyclized peptides, and reduced, linear peptides, was investigated on the basis of NMR parameters: NOEs, and 1H and 13C chemical shifts. We found that the effect of disulfide bonds on beta-hairpin stability depends on its location within the beta-hairpin structure, being very small or even destabilizing when connecting two hydrogen-bonded facing residues. When the disulfide bond is linking non-hydrogen-bonded facing residues, we estimated that its contribution to the free-energy change of beta-hairpin folding is approximately -1.0 kcal mol(-1). This value is larger than those reported for most beta-hairpin-stabilizing cross-strand side-chain-side-chain interactions, except for some aromatic-aromatic interactions, in particular the Trp-Trp one, and the cation-pi interaction between Trp and the non-natural methylated Arg/Lys. As disulfide bonds are frequently used to stabilize peptide conformations, our conclusions can be useful for peptide, peptidomimetic, and protein design, and may even extend to other chemical cross-links.

show abstract

“…This agrees well with the parallel β-sheet of equivalent length in protein structure as 13.4 and 12.9 Å on the two strands (pid:202J, chain A). We made type I and type II β-turns with the model, and compared them, respectively, with the type I β-hairpin turn found in ubiquitin (pid:1AAR, turn-seq:TLTG) (31), and the type II turn found as a subpart of the β-barrel in factor H binding protein (pid:3KVD, turn-seq:GSDD) (32) (Fig. 6C).…”

Section: Resultsmentioning

confidence: 99%

Coarse-grained, foldable, physical model of the polypeptide chain

Chakraborty

Zuckermann

2013

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

View full text Add to dashboard Cite

Although nonflexible, scaled molecular models like Pauling-Corey's and its descendants have made significant contributions in structural biology research and pedagogy, recent technical advances in 3D printing and electronics make it possible to go one step further in designing physical models of biomacromolecules: to make them conformationally dynamic. We report here the design, construction, and validation of a flexible, scaled, physical model of the polypeptide chain, which accurately reproduces the bond rotational degrees of freedom in the peptide backbone. The coarsegrained backbone model consists of repeating amide and α-carbon units, connected by mechanical bonds (corresponding to φ and ψ) that include realistic barriers to rotation that closely approximate those found at the molecular scale. Longer-range hydrogen-bonding interactions are also incorporated, allowing the chain to readily fold into stable secondary structures. The model is easily constructed with readily obtainable parts and promises to be a tremendous educational aid to the intuitive understanding of chain folding as the basis for macromolecular structure. Furthermore, this physical model can serve as the basis for linking tangible biomacromolecular models directly to the vast array of existing computational tools to provide an enhanced and interactive humancomputer interface.protein folding | self-assembly | biomimetic modular robotics | rotational energy barrier | conformational isomerism U nderstanding protein folding pathways, predicting protein structure and the de novo designing of functional proteins have been a long-standing grand challenge in computational and structural biology. Although tremendous advances are being made (1), folded protein structures are very difficult to visualize in our mind due to their complexity and shear size. State-of-the-art computer visualization techniques are well developed and provide an array of powerful interactive tools for exploring the 3D structures of biomacromolecules (2-4). While increasingly complex molecules can be visualized with computers, the mode of user interaction has been mostly limited to the mouse and keyboard. Although the use of haptic devices is on the rise, there are only a few low-cost, specialized input devices particularly designed for interaction with biomacromolecules. Augmented-reality (AR) and immersive environments enhance user interaction experiences during the handling of existing visualization tools (2, 5, 6), but the physical models used in these environments are not flexible or precise enough to represent the conformational dynamism of polypeptides by themselves. There is a strong need for scaled, realistically foldable, but inexpensive, physical models to go hand-in-hand with the AR and other computer interfaces, while concomitantly taking better advantage of current computational capabilities.Physical molecular models of organic small molecules and biomacromolecules with atomic representations have been around for many decades (7-17). Although early pioneers like...

show abstract

Natural polypeptide scaffolds: β‐sheets, β‐turns, and β‐hairpins

Cited by 41 publications

References 53 publications

Evaluating β-turn mimics as β-sheet folding nucleators

Evaluating β-turn mimics as β-sheet folding nucleators

Context‐Dependence of the Contribution of Disulfide Bonds to β‐Hairpin Stability

Coarse-grained, foldable, physical model of the polypeptide chain

Contact Info

Product

Resources

About