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 β2-microglobulin (β2m). Here we present the computational studies on two challenging models known for their enhanced amyloidogenic propensity, namely ΔN6 and D76N β2m 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.