Synergistic long-range effects of mutations underlie aggregation propensities of amylin analogues

Autor(es)

Alves, Nelson A. ^[1] ; Dias, Luis G. ^[2] ; Frigori, Rafael B. ^[3]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, FFCLRP, Dept Fis, Ave Bandeirantes 3900, BR-14040901 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, FFCLRP, Dept Quim, Ave Bandeirantes 3900, BR-14040901 Ribeirao Preto, SP - Brazil

^[3] Univ Tecnol Fed Parana, Rua Cristo Rei 19, BR-85902490 Toledo, PR - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Molecular Modeling; v. 25, n. 9 SEP 2019.
• Citações Web of Science: 0

Resumo

The USFDA has approved pramlintide, commercially named Symlin (sIAPP), as adjunctive therapy for type 2 diabetes (T2D). This analogue of the human amylin peptide (hIAPP) has triple proline substitutions typical of the rat isoform (rIAPP). Recently, it was proposed that pramlintide solubility and aggregation resistance might be improved by incorporating further mutations, as S20R, screened from the wild-type porcine isoform (pIAPP), which leads to the variant named sIAPP(+). To better elucidate how such properties might be systematically induced in rationally designed analogues, we performed comparative assessments of rIAPP, sIAPP, and sIAPP(+) using replica-exchange molecular dynamics (REMD) with an accurate combination of force field Charmm22{*} and explicit aqueous solvation TIP4P/Ew. Our thermo-structural analyses show that sIAPP exhibits a thermal conversion channel of helices ->beta-sheets resembling hIAPP. This channel is depleted in rIAPP and is absent in sIAPP(+). As a consequence, sIAPP(+) presents an overall decrease of beta-like secondary structures and an overstabilization of alpha-helices. Additionally, we observed in rIAPP and sIAPP(+) an increase in the backbone RMSF of molecular terminals and the exposed area of key residues. These structural features of sIAPP(+) suggest a nonamyloidogenic character, which is corroborated by our judicious estimate of the electrostatic component of the solvation free energy using a generalized Born model, and so it may constitute an alternative strategy to sIAPP as a peptide analogue of hIAPP. Furthermore, our findings confirm that different aggregation propensities of amylin and its analogues are synergistically modulated by long-range effects of key mutations. (AU)

• Processo FAPESP: 13/08166-5 - Química em interfaces: interações de fármacos, peptídios e enzimas com membranas modelos
• Beneficiário: Iolanda Midea Cuccovia
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 17/03204-7 - Desenvolvimento e aplicação de campo de força coarse-graining em sistemas auto-organizados
• Beneficiário: Luis Gustavo Dias
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• 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