Directing Aβ42 to adopt a conformation that is free from aggregation and cell toxicity is an attractive and viable strategy to design therapeutics for Alzheimer’s disease. Over the years, extensive...
A cationic terminal extension or tail is a common feature of many DNA-binding proteins. We show that a particular type of tail rich in proline, alanine and lysine belongs to the class of 'flexible disorder' and consists of characteristic pentapeptide repeats. Our designed peptides, (AAKKA) and (PAKKA), represent the tails of several bacterial DNA-binding proteins. Enhanced conformational sampling of these representative peptides using accelerated molecular dynamic simulations supported by circular dichroism spectroscopy and nuclear magnetic resonance studies demonstrates the role of frequent and interspersed prolines in augmenting conformational heterogeneity of the peptide backbone. Analysis of circular variance of backbone dihedral angles indicates alternating regions of relative rigidity and flexibility along the peptide sequence due to prolines. Preferred placement of lysines in the regions of higher backbone flexibility might improve DNA-binding by conformational selection. Our results could be relevant for rational de novo design of disordered peptides.
Conformations of disulfide and diselenide were compared in (Boc‐Cys/Sec‐NHMe)2 and (Boc‐Cys/Sec‐OMe)2 using X‐ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, density functional theory (DFT), and circular dichroism (CD) spectroscopy. Conformations of disulfide/diselenide in polypeptides are defined based on the sign of side chain torsion angle χ3 (–CH2–S/Se–S/Se–CH2–); negative indicates left‐handed and positive indicates right‐handed orientation. In the crystals of (Boc‐Cys‐OMe)2 and (Boc‐Sec‐OMe)2, the disulfide exhibits a left‐handed and the diselenide a right‐handed orientation. Characterization of cystine and selenocystine derivatives in solution using 1H‐NMR, natural abundant 77Se NMR, 2D‐ROESY, and chemical shift analysis coupled to DMSO titration has indicated the symmetrical nature and antiparallel orientation of Cys/Sec residues about the disulfide/diselenide bridges. Structural calculations of cystine and selenocystine derivatives using DFT further support the antiparallel orientation of Cys/Sec residues about disulfide/diselenide. The far‐ultraviolet (UV) region CD spectra of cystine and selenocystine derivatives have exhibited the negative Cotton effect (CE) for disulfide and positive for diselenide confirming the difference in the conformational preference of disulfide and diselenide. In the previously reported polymorphic structure of (Boc‐Sec‐OMe)2, the diselenide has right‐handed orientation. In the X‐ray structures of disulfide and diselenide analogues of Escherichia coli protein encoded by curli specific gene C (CgsC) retrieved from Protein Databank (PDB), disulfide has left‐handed and the diselenide right‐handed orientation. The current report provides the evidence for the local conformational difference between a disulfide and a diselenide group under unconstrained conditions, which may be useful for the rational replacement of disulfide by diselenide in polypeptide chains.
Reproducibility of multi-slice GABA-edited MRSI of the human brain recorded at 3T was investigated in 6 healthy adult volunteers, with and without a retrospective motion compensation scheme applied (MoCo). Overall reproducibility was good with improved performance when MoCo was applied (relative GABA+/tCr difference between visits: 20.8% no Moco, 10.0% with MoCo). Retrospective MoCo is a viable alternative for edited-MRSI when prospective motion correction is unavailable, at least in relatively compliant subject groups.
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