Conformational Preferences of an Amyloidogenic Peptide: IR Spectroscopy of Ac-VQIVYK-NHMe

Abstract

The (306)VQIVYK(311) sequence in the tau peptide is essential for the formation of intracellular amyloid fibrils related to Alzheimer's disease, where it forms interdigitating cross-beta-structures. The inherent conformational preferences of the capped hexapeptide Ac-VQIVYK-NHMe were characterized in the gas phase. IR/UV double-resonance spectroscopy of the peptide isolated in a cold molecular beam was used to probe the conformation of the neutral peptide. The influence of protonation at the lysine side chain was investigated at 298 K by characterizing the protonated peptide ion, Ac-VQIVYK(H(+))-NHMe, with IRMPD spectroscopy in the fingerprint and amide I/II band region in an FTICR mass spectrometer. The conformations for both neutral and protonated peptides were predicted by an extensive conformational search procedure followed by cluster analysis and then DFT calculations. Comparison of the experimental and computed IR spectra, with consideration of the relative energies, was used to assign the dominant conformations observed. The neutral peptide adopts a beta-hairpin-like conformation with two loosely extended peptide chains, demonstrating the preference of the sequence for extended beta-strand-like structures. In the protonated peptide, the lysine NH3(+) disrupts this extended conformation by binding to the backbone and induces a transition to a random-coil-like structure.

Isolated Neutral Peptides

“…When the chain goes longer, head-to-tail interactions can take place, giving rise to additional H-bonding features [98,107,134,139]. Noticeable are β-hairpins exhibiting antiparallel C10 and C14 H-bonds stabilising the chain reversal [107,134].…”

“…Few examples of large molecules for which resolved or partly resolved features have been observed. One can cite tri- [80,85,88,106,112,121,124,133,[138][139][140], tetra- [107,129,134] and pentapeptides [89,98,101,107,139], and larger systems up to gramicidins [54,79,89,108]. In all cases, in addition to the potential lack of conformational selectivity, the theoretical investigation required for the assessment is a cumbersome task, which is not always successful.…”

Self‐assembly of short peptides composed of only aliphatic amino acids and a combination of aromatic and aliphatic amino acids

“…The ability of peptides to self-assemble to form supramolecular structures has been the subject of intense research in recent years [1][2][3][4][5][6][7][8][9][10][11][12]. Assembly of peptides into highly ordered onedimensional and three-dimensional nanostructures has been of great interest in the design of electronic materials [13][14][15], tissue engineering scaffolds [16][17][18] and drug release [19,20].…”

Characterizing the Intramolecular H-bond and Secondary Structure in Methylated GlyGlyH+ with H2 Predissociation Spectroscopy

“…Vibrational spectroscopy is emerging as a powerful means with which to elucidate such structures by revealing peptide conformations and protonation sites through theoretical analysis of the observed band patterns [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. This spectroscopic data is most often available through the integration of tunable infrared laser photodissociation with mass spectrometry and, in most cases, spectra of the mass-selected ions are obtained under ambient temperature conditions using infrared multiple photon dissociation (IRMPD) [28][29][30][31][32][33]. A recent variation on this scheme [34], yielding a resolution enhancement of 5 to 10 times that which is typically reported, involves cooling the ions close to 10 K [35][36][37] and "tagging" them with a weakly bound mass "messenger" using cryogenic ion trapping techniques [38][39][40].…”