Halogenation of the N‐Terminus Tyrosine 10 Promotes Supramolecular Stabilization of the Amyloid‐β Sequence 7–12

Abstract

Here, we demonstrate that introduction of halogen atoms at the tyrosine 10 phenol ring of the DSGYEV sequence derived from the flexible amyloid‐β N‐terminus, promotes its self‐assembly in the solid state. In particular, we report the crystal structures of two halogen‐modified sequences, which we found to be stabilized in the solid state by halogen‐mediated interactions. The structural study is corroborated by Non‐Covalent Interaction (NCI) analysis. Our results prove that selective halogenation of an amino acid enhances the supramolecular organization of otherwise unstructured biologically‐relevant sequences. This method may develop as a general strategy for stabilizing highly polymorphic peptide regions.

A Step toward the Quantification of Noncovalent Interactions in Large Biological Systems: The Independent Gradient Model-Extremely Localized Molecular Orbital Approach

“…This could become extremely advantageous in view of a possible future use of the IGM-ELMO method in the context of virtual high-throughput screenings (vHTS) or docking calculations for the rational design of new drugs. To accomplish this task, we considered the dimers of two halogenated polypeptides deriving from the bromination and chlorination of the tyrosine residue in position Y10 of the sequence 7-12 (DSGYEV) of the flexible amyloid-β (Aβ) peptide . For the sake of precision, we point out that, in those cases, only two hydrogen atoms of tyrosine are substituted with halogens, namely, those at the ortho-positions with respect to the hydroxyl group in the aromatic ring of tyrosine.…”

“…From the X-ray crystal structures of the brominated and chlorinated peptides (from now on also indicated as DSGY(Br)EV and DSGY(Cl)EV, respectively), 58 we extracted dimers (170 atoms) characterized by a π − π interaction between the aromatic rings of the halogenated tyrosine residues (for the structures of the dimers, see Figure 4 and Figure S6 in the Supporting Information). For each of them, we also substituted the halogen with hydrogen atoms using the software MolProbity (see the section dedicated to the Computational Details in Appendix for more details).…”

Emergence of Elastic Properties in a Minimalist Resilin‐Derived Heptapeptide upon Bromination

“…[ 8 ] More recently, halogenation of tyrosine residues also proved to be effective in the supramolecular stabilization of highly polymorphic and structurally flexible peptide sequences, [ 9–14 ] such as the A β N ‐term region (i.e., DSGYEV), which is not fibrillogenic unless halogenated. [ 15,16 ] In these systems, halogen atoms were found to boost their self‐assembling capability enriching their interaction patterns with halogen bonds (XBs), that is, intermolecular interactions wherein halogen atoms function as electron acceptors. [ 17 ] In particular, XBs usually take place between introduced halogen atoms and backbone amide oxygen of a close by peptide chain, thus strengthening the β‐sheet structural core of amyloid fibrils known as the “steric zipper.” [ 8 ] Given the capability of halogen atoms to promote supramolecular order in amyloidogenic peptides and the enhanced elastic moduli showed by brominated tissues of marine organisms, we moved to explore the possible induction of elastomeric properties in short peptides upon halogenation.…”

Iodinated Diketopiperazines: Synthesis and Biological Evaluation of Iodinated Analogues of Cyclo(L‐Tyrosine‐L‐Tyrosine) Peptides

“…[10][11][12][13] The halogenated tyrosine has been implicated for the structural stabilization of the peptide secondary structure. [14][15][16] The synthetic incorporation of iodine in the tyrosine side chain has been used as a protein labelling technique for its structural and functional studies. [17] The iodinated tyrosine is also employed effectively to remedy the phase problem in the field of protein X-ray crystallography.…”

“…Therefore, halogenated aromatic amino acids represent an important class of building blocks, which have been utilized for various applications [10–13] . The halogenated tyrosine has been implicated for the structural stabilization of the peptide secondary structure [14–16] . The synthetic incorporation of iodine in the tyrosine side chain has been used as a protein labelling technique for its structural and functional studies [17] .…”