  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.
