Computational modelling of supramolecular metallopeptide assemblies.

Among the important questions in supramolecular peptide self-assemblies are their interactions with metallic compounds and ions. In the last decade, intensive efforts have been devoted to understanding the structural properties of these interactions including their dynamical and catalytic impact in natural and de novo systems. Since structural insights from experimental approaches could be particularly challenging, computational chemistry methods are interesting complementary tools.

Computational Study of Amyloidβ Familial Mutations and Metal Interaction: Impact on Monomers and Aggregates Dynamical Behaviors.

One of the main hallmarks of Alzheimer's Disease is the formation of β-amyloid plaques, whose formation may be enhanced by metal binding or the appearance of familial mutations. In the present study, the simultaneous effect of familial mutations (E22Q, E22G, E22K, and D23N) and binding to metal ions (Cu(II) or Al(III)) is studied at the Aβ monomeric and fibrillar levels. With the application of GaMD and MD simulations, it is observed that the effects of metal binding and mutations differ in the monomeric and fibrillar forms.

Amyloid Fibrils Formed by Short Prion-Inspired Peptides Are Metalloenzymes.

Enzymes typically fold into defined 3D protein structures exhibiting a high catalytic efficiency and selectivity. It has been proposed that the earliest enzymes may have arisen from the self-assembly of short peptides into supramolecular amyloid-like structures. Several artificial amyloids have been shown to display catalytic activity while offering advantages over natural enzymes in terms of modularity, flexibility, stability, and reusability.

Computational assessment of the impact of Cu(II) and Al(III) on β-amyloid fibrils: Binding sites, structural stability, and possible physiological implications.

One of Alzheimer's disease major hallmarks is the aggregation of β-amyloid peptide, a process in which metal ions play an important role. In the present work, an integrative computational study has been performed to identify the metal-binding regions and determine the conformational impact of Cu(II) and Al(III) ion binding to the β-amyloid (Aβ) fibrillary structure. Through classical and Gaussian accelerated molecular dynamics, it has been observed that the metal-free fiber shows a hinge fan-like motion of the S-shaped structure, maintaining the general conformation.

Controlling oncogenic KRAS signaling pathways with a Palladium-responsive peptide.

RAS oncoproteins are molecular switches associated with critical signaling pathways that regulate cell proliferation and differentiation. Mutations in the RAS family, mainly in the KRAS isoform, are responsible for some of the deadliest cancers, which has made this protein a major target in biomedical research. Here we demonstrate that a designed bis-histidine peptide derived from the αH helix of the cofactor SOS1 binds to KRAS with high affinity upon coordination to Pd(II).

Impact of Cu(II) and Al(III) on the conformational landscape of amyloidβ.

Metal ions have been found to play an important role in the formation of extracellular β-amyloid plaques, a major hallmark of Alzheimer's disease. In the present study, the conformational landscape of Aβ42 with Al(iii) and Cu(ii) has been explored using Gaussian accelerated molecular dynamics. Both metals reduce the flexibility of the peptide and entail a higher structural organization, although to different degrees.

BioMetAll: Identifying Metal-Binding Sites in Proteins from Backbone Preorganization.

With a large amount of research dedicated to decoding how metallic species bind to proteins, in silico methods are interesting allies for experimental procedures. To date, computational predictors mostly work by identifying the best possible sequence or structural match of the target protein with metal-binding templates. These approaches are fundamentally focused on the first coordination sphere of the metal.

Dynamic Stereoselection of Peptide Helicates and Their Selective Labeling of DNA Replication Foci in Cells*.

Although largely overlooked in peptide engineering, coordination chemistry offers a new set of interactions that opens unexplored design opportunities for developing complex molecular structures. In this context, we report new artificial peptide ligands that fold into chiral helicates in the presence of labile metal ions such as Fe and Co . Heterochiral β-turn-promoting sequences encode the stereoselective folding of the peptide ligands and define the physicochemical properties of their corresponding metal complexes.