Conformational switches, peptide

Yang JJ, Pitkeathly M, Radford SE (1994) Far-uv circular-dichroism reveals a conformational switch in a peptide fragment Irom the beta-sheet of hen lysozyme. Biochemistry 33 7345-7353... 

A similar peptidic conformational switch was developed by Mutter and Hersperger [9]. In that work, they showed that the 15-residue peptide 7 could have its conformation modulated by the polarity of the solvent (Fig. 6). Indeed, peptide 7 was shown to adopt an a-helical structure in trifluoroethanol and... 

Based on very similar principles, though more recently, Suzuki and Fujii (1999) designed a helix-loop-helix peptide. On a related theme, the aforementioned design from Pandya et al. (2004) for a helix-loop-helix peptide stabilized by a disulfide bridge used similar ideas, although the final sequence was very different from the Myszka and Chaiken and the Suzuki and Fujii peptides, as it was also made compatible with a parallel coiled-coil dimer to promote conformational switching. 

Mutter, M., Chandravarkar, A., Boyat, C., Lopez, J., Dos Santos, S., Mandal, B., Mimna, R., Murat, K., Patiny, L., and Saucede, L. "Switch peptides in statu nascendi induction of conformational transitions relevant to degenerative diseases". Angew. Chem. Int. Ed. 43(32), 4172-4178 (2004). 

NMR spectroscopy can detect the conformational dynamics, which are also referred to as conformational switching of RNA molecules that coexist in different stable states. Solid-state NMR spectroscopy investigates molecules as powders or crystals and has become a powerful tool for the investigation of membrane proteins and their complexes with small peptide agonists. In addition, protein amyloid fibers and polymers can be investigated. 

The benzylamino residue in 25 is immersed into the CD cavity prior to complexa-tion of the phenyl ring, as evident from NMR analyses. Complexation with a peptide then requires that this intramolecular association must be given up, which explains why the affinity is not increased by possible lipophilic interactions of aromatic peptide side chains and the benzyl group outside the cavity. The conformational switching triggered by complexation with a peptide was followed by suitable NMR experiments, and is supported by computer-aided molecular modeling (see our website). 

Fig. 11.20 The concept of switch-peptides [207,208] in situ induction of conformational changes by enzyme-triggered acyl migration results in the nucleation of a helix (left) or a c/s-amide bond-induced kink conformation (right) for the breaking of/i-sheet templates (e.g. amyloid fibrils).

In addition to their use in the in situ induction of conformational transitions, switch-peptides (O-acyl isopeptides) may serve as alternative solubilizing technique in peptide synthesis [207-214]. The elaboration of these concepts, notably the rational design of dynamic pharmacophores as new type of therapeutically useful compounds, is the subject of our current research. 

Wang W, Hecht MH (2002) Rationally designed mutations convert de novo amyloid-like fibrils into monomeric beta-sheet proteins. Proc Natl Acad Sci USA 99 2760-2765 Watson AA, FairUe DP, Craik DJ (1998) Solution structure of methionine-oxidized amyloid beta.-peptide (1 0). Does oxidation affect conformational switching Biochemistry 37 12700-12706 Waugh DF (1957) A mechanism for the formation of fibrils from protein molecules. J Cell Physiol 49 145-164... 

Template-o , which is a designed coiled coil. To encourage a conformational switch, residues at / positions were changed from glutamine to threonine to produce Template-ofT. Below 70 °C, the peptide is cK-helical and above this temperature it forms -structured amyloid-like fibrils. Cross-linking the peptides to achieve a )8-hairpin-like conformation increases amyloid fibril formation. 

A later paper details the de novo design of peptides that switch between a coiled-coil and a helical-hairpin conformation. The parent peptide (coiled-coil switch peptide) CSP-1 is a parallel dimeric coiled coil, but oxidation of cysteine residues in (he peptide causes the switch to a monomer. It remains ar-helical, although the a-helical content is low. Increasing the loop length gives CSP-3, which is a peptide with a higher helical content. CSP-6, an anagram of CSP-3, is more helical stUl and can be switched between the helical-hairpin and coiled-coil conformations. 

Water may play other roles for instance, in the conformational switch from one turn conformation to another with the opposite twist in the peptide catalyst 3, causing a reversal in enantioselectivity upon addition of water (up to 50%) to DMSO (Scheme 24.3) [21]. Such a switch of enantioselectivity of a given catalyst by changes of solvent is unusual, but a few reports have been described [22]. 

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