Topologically non-trivial metal-organic assemblies inhibit β2-microglobulin amyloidogenesis

Abstract

Inhibiting amyloid aggregation through high-turnover dynamic interactions could be an efficient strategy that is already used by small heat-shock proteins in different biological contexts. We report the interactions of three topologically non-trivial, zinc-templated metal-organic assemblies, a [2]catenane, a trefoil knot (TK), and Borromean rings, with two β 2 -microglobulin (β2m) variants responsible for amyloidotic pathologies. Fast exchange and similar patterns of preferred contact surface are observed by NMR, consistent with molecular dynamics simulations. In vitro fibrillation is inhibited by each complex, whereas the zinc-free TK induces protein aggregation and does not inhibit fibrillogenesis. The metal coordination imposes structural rigidity that determines the contact area on the β2m surface depending on the complex dimensions, ensuring in vitro prevention of fibrillogenesis. Administration of TK, the best protein-contacting species, to a disease-model organism, namely a Caenorhabditis elegan s mutant expressing the D76N β2m variant, confirms the bioactivity potential of the knot topology and suggests new developments. Topologically non-trivial (TnT) species may engage labile supramolecular interactions Proteins can be ideal targets of TnT metal-templated structures Protein fibrillogenesis can be inhibited by TnT metal-organic assemblies Rigidity and dimensions of the TnT assemblies modulate interactions with proteins Prakasam et al. report that topologically non-trivial metal-organic species inhibit the in vitro fibrillogenesis of the paradigmatic amyloidogen β 2 -microglobulin and the effects of the D76N mutant expression in a Caenorhabditis elegans disease model. Acting as small-molecule chaperones, the metal-templated assemblies suppress the formation of soluble protofibrillar oligomers by engaging labile supramolecular interactions that interfere with protein-protein pairing.