Citrate stabilized gold nanoparticles interfere with amyloid fibril formation: D76N and {\Delta}N6 \b{eta}2-microglobulin variants

TL;DR

This study uses computational and experimental methods to show that citrate-coated gold nanoparticles can disrupt early protein aggregation stages, preventing amyloid fibril formation in disease-related protein variants.

Contribution

It reveals a detailed molecular mechanism by which citrate-coated gold nanoparticles inhibit amyloidogenic protein dimerization and fibril formation, combining simulations and NMR data.

Findings

Citrate-coated gold nanoparticles disassemble protein dimers.

Nanoparticles inhibit amyloid fibril formation.

Experimental validation confirms computational predictions.

Abstract

Protein aggregation including the formation of dimers and multimers in solution, underlies an array of human diseases such as systemic amyloidosis which is a fatal disease caused by misfolding of native globular proteins damaging the structure and function of affected organs. Different kind of interactors can interfere with the formation of protein dimers and multimers in solution. A very special class of interactors are nanoparticles thanks to the extremely efficient extension of their interaction surface. In particular citrate-coated gold nanoparticles (cit-AuNPs) were recently investigated with amyloidogenic protein $\beta$2-microglobulin ($\beta$2m). Here we present the computational studies on two challenging models known for their enhanced amyloidogenic propensity, namely $\Delta$N6 and D76N $\beta$2m naturally occurring variants, and disclose the role of cit-AuNPs on their fibrillogenesis. The proposed interaction mechanism lies in the interference of the cit-AuNPs with the protein dimers at the early stages of aggregation, that induces dimer disassembling. As a consequence, natural fibril formation can be inhibited. Relying on the comparison between atomistic simulations at multiple levels (enhanced sampling molecular dynamics and Brownian dynamics) and protein structural characterisation by NMR, we demonstrate that the cit-AuNPs interactors are able to inhibit protein dimer assembling. As a consequence, the natural fibril formation is also inhibited, as found in experiment.