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Article

The Early Phase of β2m Aggregation: An Integrative Computational Study Framed on the D76N Mutant and the ΔN6 Variant

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BioISI—Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
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BioISI—Biosystems & Integrative Sciences Institute and Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
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Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
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BioISI—Biosystems & Integrative Sciences Institute and Departamento de Física, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
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Author to whom correspondence should be addressed.
Biomolecules 2019, 9(8), 366; https://doi.org/10.3390/biom9080366
Received: 27 July 2019 / Revised: 8 August 2019 / Accepted: 13 August 2019 / Published: 14 August 2019
(This article belongs to the Section Molecular Structure and Dynamics)
Human β2-microglobulin (b2m) protein is classically associated with dialysis-related amyloidosis (DRA). Recently, the single point mutant D76N was identified as the causative agent of a hereditary systemic amyloidosis affecting visceral organs. To get insight into the early stage of the β2m aggregation mechanism, we used molecular simulations to perform an in depth comparative analysis of the dimerization phase of the D76N mutant and the ΔN6 variant, a cleaved form lacking the first six N-terminal residues, which is a major component of ex vivo amyloid plaques from DRA patients. We also provide first glimpses into the tetramerization phase of D76N at physiological pH. Results from extensive protein–protein docking simulations predict an essential role of the C- and N-terminal regions (both variants), as well as of the BC-loop (ΔN6 variant), DE-loop (both variants) and EF-loop (D76N mutant) in dimerization. The terminal regions are more relevant under acidic conditions while the BC-, DE- and EF-loops gain importance at physiological pH. Our results recapitulate experimental evidence according to which Tyr10 (A-strand), Phe30 and His31 (BC-loop), Trp60 and Phe62 (DE-loop) and Arg97 (C-terminus) act as dimerization hot-spots, and further predict the occurrence of novel residues with the ability to nucleate dimerization, namely Lys-75 (EF-loop) and Trp-95 (C-terminus). We propose that D76N tetramerization is mainly driven by the self-association of dimers via the N-terminus and DE-loop, and identify Arg3 (N-terminus), Tyr10, Phe56 (D-strand) and Trp60 as potential tetramerization hot-spots. View Full-Text
Keywords: protein folding; intermediate states; protein aggregation; protein–protein docking; molecular dynamics; Monte Carlo protein folding; intermediate states; protein aggregation; protein–protein docking; molecular dynamics; Monte Carlo
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MDPI and ACS Style

J. S. Loureiro, R.; Vila-Viçosa, D.; Machuqueiro, M.; Shakhnovich, E.I.; F. N. Faísca, P. The Early Phase of β2m Aggregation: An Integrative Computational Study Framed on the D76N Mutant and the ΔN6 Variant. Biomolecules 2019, 9, 366. https://doi.org/10.3390/biom9080366

AMA Style

J. S. Loureiro R, Vila-Viçosa D, Machuqueiro M, Shakhnovich EI, F. N. Faísca P. The Early Phase of β2m Aggregation: An Integrative Computational Study Framed on the D76N Mutant and the ΔN6 Variant. Biomolecules. 2019; 9(8):366. https://doi.org/10.3390/biom9080366

Chicago/Turabian Style

J. S. Loureiro, Rui, Diogo Vila-Viçosa, Miguel Machuqueiro, Eugene I. Shakhnovich, and Patrícia F. N. Faísca. 2019. "The Early Phase of β2m Aggregation: An Integrative Computational Study Framed on the D76N Mutant and the ΔN6 Variant" Biomolecules 9, no. 8: 366. https://doi.org/10.3390/biom9080366

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