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Article

Computational Analysis of the Interactions between the S100B Extracellular Chaperone and Its Amyloid β Peptide Client

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Biosystems and Integrative Sciences Institute, Faculdade de Ciências, Universidade Lisboa, 1749-016 Lisbon, Portugal
2
Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade Lisboa, 1749-016 Lisbon, Portugal
*
Authors to whom correspondence should be addressed.
Academic Editor: Botond Penke
Int. J. Mol. Sci. 2021, 22(7), 3629; https://doi.org/10.3390/ijms22073629
Received: 4 March 2021 / Revised: 24 March 2021 / Accepted: 27 March 2021 / Published: 31 March 2021
S100B is an astrocytic extracellular Ca2+-binding protein implicated in Alzheimer’s disease, whose role as a holdase-type chaperone delaying Aβ42 aggregation and toxicity was recently uncovered. Here, we employ computational biology approaches to dissect the structural details and dynamics of the interaction between S100B and Aβ42. Driven by previous structural data, we used the Aβ25–35 segment, which recapitulates key aspects of S100B activity, as a starting guide for the analysis. We used Haddock to establish a preferred binding mode, which was studied with the full length Aβ using long (1 μs) molecular dynamics (MD) simulations to investigate the structural dynamics and obtain representative interaction complexes. From the analysis, Aβ-Lys28 emerged as a key candidate for stabilizing interactions with the S100B binding cleft, in particular involving a triad composed of Met79, Thr82 and Glu86. Binding constant calculations concluded that coulombic interactions, presumably implicating the Lys28(Aβ)/Glu86(S100B) pair, are very relevant for the holdase-type chaperone activity. To confirm this experimentally, we examined the inhibitory effect of S100B over Aβ aggregation at high ionic strength. In agreement with the computational predictions, we observed that electrostatic perturbation of the Aβ-S100B interaction decreases anti-aggregation activity. Altogether, these findings unveil features relevant in the definition of selectivity of the S100B chaperone, with implications in Alzheimer’s disease. View Full-Text
Keywords: protein interactions; molecular dynamics; docking; chaperones; protein aggregation; amyloids; protein folding diseases protein interactions; molecular dynamics; docking; chaperones; protein aggregation; amyloids; protein folding diseases
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MDPI and ACS Style

Rodrigues, F.E.P.; Figueira, A.J.; Gomes, C.M.; Machuqueiro, M. Computational Analysis of the Interactions between the S100B Extracellular Chaperone and Its Amyloid β Peptide Client. Int. J. Mol. Sci. 2021, 22, 3629. https://doi.org/10.3390/ijms22073629

AMA Style

Rodrigues FEP, Figueira AJ, Gomes CM, Machuqueiro M. Computational Analysis of the Interactions between the S100B Extracellular Chaperone and Its Amyloid β Peptide Client. International Journal of Molecular Sciences. 2021; 22(7):3629. https://doi.org/10.3390/ijms22073629

Chicago/Turabian Style

Rodrigues, Filipe E.P., António J. Figueira, Cláudio M. Gomes, and Miguel Machuqueiro. 2021. "Computational Analysis of the Interactions between the S100B Extracellular Chaperone and Its Amyloid β Peptide Client" International Journal of Molecular Sciences 22, no. 7: 3629. https://doi.org/10.3390/ijms22073629

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