Title: Citrate stabilized gold nanoparticles interfere with amyloid fibril formation: D76N and ΔN6 β2-microglobulin variants

Abstract

Here, 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 formationmore » is also inhibited, as found in experiment.« less

Authors:

Brancolini, Giorgia  ^[1];

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• Search DOE PAGES for ORCID "0000-0002-1083-9198"
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Maschio, Maria Celeste  ^[1];

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• Search DOE PAGES for ORCID "0000-0002-2003-211X"
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Cantarutti, Cristina ^[2]; Corazza, Alessandra ^[3]; Fogolari, Federico  ^[3];

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• Search DOE PAGES for ORCID "0000-0001-9862-250X"
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Bellotti, Vittorio ^[4]; Corni, Stefano ^[5]; Esposito, Gennaro  ^[6]

• Search DOE PAGES for author "Esposito, Gennaro"
• Search DOE PAGES for ORCID "0000-0001-9353-5423"
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+ Show Author Affiliations

1. CNR Institute Nanoscience, Modena (Italy)
2. Univ. of Udine, Udine (Italy)
3. Univ. of Udine, Udine (Italy); Istituto Nazionale Biostrutture e Biosistemi, Roma (Italy)
4. Univ. di Pavia, Pavia (Italy); Istituto Nazionale Biostrutture e Biosistemi, Roma (Italy); Univ. College of London, London (United Kingdom)
5. Univ. of Padova, Padova (Italy); CNR Institute Nanoscience, Modena (Italy)
6. CNR Institute Nanoscience, Modena (Italy); Istituto Nazionale Biostrutture e Biosistemi, Roma (Italy); New York Univ. at Abu Dhabi, Abu Dhabi (United Arab Emirates)

Publication Date:

2018-02-14

Research Org.:

Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Org.:

USDOE Office of Science (SC), Basic Energy Sciences (BES)

OSTI Identifier:

1493591

Grant/Contract Number:  

AC02-05CH11231

Resource Type:

Accepted Manuscript

Journal Name:

Nanoscale

Additional Journal Information:

Journal Volume: 10; Journal Issue: 10; Journal ID: ISSN 2040-3364

Publisher:

Royal Society of Chemistry

Country of Publication:

United States

Language:

English

Subject:

60 APPLIED LIFE SCIENCES