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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

In Silico Comparative Study of Human and Porcine Amylin

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Autor(es):
Alves, Nelson A. [1] ; Frigori, Rafael B. [2]
Número total de Autores: 2
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, FFCLRP, Dept Fis, Ave Bandeirantes 3900, BR-14040901 Ribeirao Preto, SP - Brazil
[2] Univ Tecnol Fed Parana, Rua Cristo Rei 19, BR-85902490 Toledo, PR - Brazil
Número total de Afiliações: 2
Tipo de documento: Artigo Científico
Fonte: Journal of Physical Chemistry B; v. 122, n. 47, p. 10714-10721, NOV 29 2018.
Citações Web of Science: 1
Resumo

Islet transplantation is a promising treatment for type 2 diabetes, but its success is impaired by progressive graft loss, likely due to cytotoxic aggregation of the hormone human islet amyloid polypeptide (IAPP) secreted by the endocrine pancreas. Alternatively, the effectiveness of porcine xenotransplantations might be explained by the fibrillization-resistance of the porcine mutant. To better elucidate such molecular mechanisms, we performed comparative replica-exchange molecular dynamics simulations of both human (hIAPP) and porcine (pIAPP) isoforms. The accurate force field Charmm22{*} with explicit aqueous solvation TIP4P/Ew ensured a minimal structural bias around physiological temperatures. Along which, the peptides are shown to present no structural-phase transition of folding from a microcanonical thermodynamics perspective. Both IAPP isoforms predominantly exhibit random coil structures, but in a minor percentage we observed a direct alpha-helix -> beta-sheet thermal conversion during the folding process of hIAPP, which is absent in pIAPP. The amyloidogenic segment 20-29 in pIAPP, which hosts 5 out of the 10 overall mutations found in this peptide, is strongly depleted of beta-sheet structures in constrast to hIAPP. Hydrogen bond analysis revealed a predominant frequency of 3-helix contacts in this residue range for pIAPP. These features of pIAPP anticorrelate with the presence of a well-known beta-sheet rich monomeric state that in hIAPP acts as an intermediate inducing oligomerization. (AU)

Processo FAPESP: 16/04176-4 - Análise sistemática in silico do comportamento crítico do peptídeo amiloide beta e de alguns dos seus mutantes
Beneficiário:Nelson Augusto Alves
Modalidade de apoio: Auxílio à Pesquisa - Regular