Metal-Ion Modulated Structural Transformation of Amyloid-Like Dipeptide Supramolecular Self-Assembly

Abstract

The misfolding of proteins and peptides potentially leads to a conformation transition from an αhelix or random coil to β-sheet-rich fibril structures, which are associated with various amyloid degenerative disorders. Inhibition of the β-sheet aggregate formation and control of the structural transition could therefore attenuate the development of amyloid-associated diseases. However, the structural transitions of proteins and peptides are extraordinarily complex processes that are still not fully understood and thus challenging to manipulate. To simplify this complexity, herein, the effect of metal ions on the inhibition of amyloid-like β-sheet dipeptide selfassembly is investigated. By changing the type and ratio of the metal ion/dipeptide mixture, structural transformation is achieved from a β-sheet to a superhelix or random coil, as confirmed by experimental results and computational studies. Furthermore, the obtained supramolecular metallogel exhibits excellent in vitro DNA binding and diffusion capability due to the positive charge of the metal/dipeptide complex. This work may facilitate the understanding of the role of metal ions in inhibiting amyloid formation and broaden the future applications of supramolecular metallogels in three-dimensional (3D) DNA biochip, cell culture, and drug delivery.

Recent advances in short peptide self-assembly: from rational design to novel applications

“…Recently, Ji et al [38] [40]. Stupp et al [41] showed that hydrogen bonding, π-π, and hydrophobic interactions all tend to promote the aggregation of amphiphilic peptide molecules, whereas electrostatic repulsion causes their disassociation.…”

Ultrashort Peptide Self-Assembly: Front-Runners to Transport Drug and Gene Cargos

“…Different chemical reactions are employed to construct selfassembled nanostructures . A general approach followed by peptide chemists is to incorporate modifications in the form of easy and reversible cleavable appropriate moieties/groups at the carbonyl-nitrogen bond (readily cleavable urethanes containing appropriate alkyl groups such as benzyl and tert-butyl liberating the amino groups), incorporating alkyl spacers of various lengths to modulate the chirality (Panda et al, 2019), π-clamping to tune the reactivity , backbone amide modifications for peptidomimetic hydrogelators with enhanced stability and mechanical properties compared to peptide hydrogelators (Basavalingappa et al, 2019), enforcing a conformational constraint to prevent β-sheet structure (Bowerman and Nilsson, 2010), formulated sequence patterns to optimize charge distribution for conjugating bioactive cargo , alternating d/l-chirality for 1D-to 2D-selfassembly (Insua and Montenegro, 2019), a racemic mixture of the mirror-image peptides to provide more rigidity to the gel (Nagy-Smith et al, 2017), alternative hydrophobic and hydrophilic residues for catalytic activity (Song et al, 2018), coordination with metal ions to inhibit amyloid-like structure (Ji et al, 2019), fine-tune assembly for hydrogel (Loic, 2017) and so on. N-Acetylation (compound attached to the amino; N-terminus) and C-amidation (compound attached to the carboxyl; C-terminus) is the most usual policy to stabilize nearly all categories of peptides.…”

“…The molecular mechanism build on density functional theory, advised by González-Díaz et al recommends the position of the side chain, where it branches, during crystallization, to be the determining factor to drive the dipeptides into either hydrophobic or hydrophilic channels (González-Díaz et al, 2019). The structural transformation of a dipeptide self-assembly just by changing the types/ratios of the metal ion or the dipeptide to inhibit amyloid-like structure has been presented by Ji et al (2019).…”

Ordered Nanofibers Fabricated from Hierarchical Self‐Assembling Processes of Designed α‐Helical Peptides

“…As a result, metal ions have been widely exploited to promote peptide self-assembly in vitro and for the de novo design of functional proteins. [26,[49][50][51][52][53][54][55][56][57][58] In these cases, metal ion complexation serves as a force distinct from the non-covalent interactions already discussed in specific binding ligands and preferred coordination geometry. By substituting two His residues for the two Asn residues of NN, we expect the self-assembly of HH to be controlled by metal-ion coordination in the hydrophobic interface instead of specific Asn-Asn interactions.…”