Directed Self-Assembly of Trimeric DNA-Bindingchiral Miniprotein Helicates

Abstract

We propose that peptides are highly versatile platforms for the precise design of supramolecular metal architectures, and particularly, for the controlled assembly of helicates. In this context, we show that the bacteriophage T4 Fibritin foldon (T4Ff) can been engineered on its N-terminus with metal-chelating 2,2′-bipyridine units that stereoselectively assemble in the presence of Fe(II) into parallel, three-stranded peptide helicates with preferred helical orientation. Modeling studies support the proposed self-assembly and the stability of the final helicate. Furthermore, we show that these designed mini-metalloproteins selectively recognize three-way DNA junctions over double-stranded DNA.

Metallohelices emulate the properties of short cationic α-helical peptides

“… 36,39 Vázquez and co-workers reported an elegant diastereoselective self-assembly approach to bimetallic asymmetric helical architectures. 40–42 Solid-phase peptide synthesis was used to afford the carefully designed single ligand strand in self-assembling metallopeptide 16 . Bipyridine units are included for metal coordination, and two proline units create the hairpin turns and encode the sense of helical chirality.…”

Cavity-Containing [Fe2L3]4+ Helicates: An Examination of Host-Guest Chemistry and Cytotoxicity

“…The biological properties of the Fe(II) and Ru(II) systems were poor but the more robust Co(III) helicates were shown to bind to and condense DNA and in addition displayed good anticancer activity (Crlikova et al, 2020). Di(2,2′-bipyridine) ligands (Glasson et al, 2008;Glasson et al, 2011a;Glasson et al, 2011b) (Gamba et al, 2014;Gómez-González et al, 2018;Gomez-Gonzalez et al, 2021).…”

“…The biological properties of the Fe(II) and Ru(II) systems were poor but the more robust Co(III) helicates were shown to bind to and condense DNA and in addition displayed good anticancer activity ( Crlikova et al, 2020 ). Di(2,2′-bipyridine) ligands ( Glasson et al, 2008 ; Glasson et al, 2011a ; Glasson et al, 2011b ) have also been used to generate [M 2 L 3 ] 4+ triple-stranded helicates and recently Vázquez and co-workers have examined the DNA binding and cytotoxicity of some peptide linked [M 2 L 3 ] 4+ helicates [where M = Fe(II) or Co(III)] ( Gamba et al, 2014 ; Gómez-González et al, 2018 ; Gomez-Gonzalez et al, 2021 ).…”

Engineering mono- and multi-valent inhibitors on a modular scaffold

“…56 In order to further extend the multivalent capabilities and to produce more complex binding geometries beyond what is possible with the linearly arrayed nTBP-CTPR2n format, we engineered a trimeric 'foldon' motif into the constructs (nTBP-CTPR2n-foldon). [57][58][59][60][61] Our results highlight the power of multivalent inhibitors for targeting complex protein-protein interactions, where occupancy-driven inhibition using simple monovalent molecules is unlikely to be effective.…”