Conformational switches, peptide structures

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... 

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. 

This result is in stark contrast to a study of Moyna et alf who applied nearly the same formalism for calculating the proton chemical shifts [Eq. (40)]. For the tripeptide under investigation only a limited set of intra-residue proton distances was available. The definition of structure was therefore greatly improved when the proton chemical shift constraints were switched on. The chemical shift refinement reduced the rmsd for the backbone atoms from 1.2 A to 0.2 A, and it revealed a single set of conformers with both peptide bonds in trans conformation. The shift constraints drove the molecule energetically uphill by 3.9 kcal/mol but produced a well-defined minimum within the energy hyper-surface. Obviously, chemical shift constraints will produce well-defined structures when other constraints are not available from experiment. 

Chemical shift target functions proved their power especially in the refinement of smaller peptides as for example a vasopressin derivative.Using only traditional constraints, this cyclic peptide switched in MD simulations between two conformations. h chemical shift constraints forced the structure into a single conformation that not only fits the chemical shift constraints well but also satisfies the NOE constraints better than in their absence. Despite the fact that the accuracy of this type of chemical shift calculation for protons is still relatively low (about 0.25 ppm), chemical shift constraints can significantly reduce the conformational space allowed for the structures. 

The concept of cis-trans (Z-E) isomerism, originally used for the description of the relative geometry of olefins, has been extended to many other functions which feature a double bond character (pseudo double bonds), such as amides, as well as single bonds with a partial or complete limited rotation due to steric or stereoelec-tronic effects. Cis-trans isomerization (CTI) therefore exists in non-re-bonded or overcrowded molecules that switch from a given stable conformational state to another. This is the case of biaryl compounds which have been utilized in organic chemistry as the basis of molecular switches and rotors [1,2]. Nature has also exploited CTI of single bonds to increasing molecular diversity, in particular with the bulky thyroxin, a thyroid hormone, and the well-known disulfide bond which plays a critical role in the structure of peptides and in the conformation of proteins. 

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