TY - JOUR
T1 - Citrate stabilized gold nanoparticles interfere with amyloid fibril formation
T2 - D76N and Δn6 β2-microglobulin variants
AU - Brancolini, Giorgia
AU - Maschio, Maria Celeste
AU - Cantarutti, Cristina
AU - Corazza, Alessandra
AU - Fogolari, Federico
AU - Bellotti, Vittorio
AU - Corni, Stefano
AU - Esposito, Gennaro
N1 - Funding Information:
MIUR through PRIN 2012A7LMS3-003 is gratefully acknowledged. S. C. acknowledges funding from ERC under the grant ERC-CoG-681285 TAME-Plasmons. The ISCRA staff at CINECA (Bologna, Italy) is acknowledged for computational facilities and technical support. Oak Ridge National Laboratory by the Scientific User Facilities Division, Office of Basic Energy Sciences, U.S. Department of Energy is acknowledged for the supercomputing project CNMS2013-064. Facilities of the National Energy Research Scientific Computing Center (NERSC), which is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231.
Funding Information:
Funding from MIUR through PRIN 2012A7LMS3_003 is gratefully acknowledged. S. C. acknowledges funding from ERC under the grant ERC-CoG-681285 TAME-Plasmons. The ISCRA staff at CINECA (Bologna, Italy) is acknowledged for computational facilities and technical support. Oak Ridge National Laboratory by the Scientific User Facilities Division, Office of Basic Energy Sciences, U.S. Department of Energy is acknowledged for the supercomputing project CNMS2013-064. Facilities of the National Energy Research Scientific Computing Center (NERSC), which is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231, are also acknowledged.
Publisher Copyright:
© 2018 The Royal Society of Chemistry.
PY - 2018/3/14
Y1 - 2018/3/14
N2 - 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.
AB - 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.
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U2 - 10.1039/c7nr06808e
DO - 10.1039/c7nr06808e
M3 - Article
C2 - 29469914
AN - SCOPUS:85043520762
SN - 2040-3364
VL - 10
SP - 4793
EP - 4806
JO - Nanoscale
JF - Nanoscale
IS - 10
ER -