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

Author(s)

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

Affiliation

^[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

• Document type: Journal article
• Source: Journal of Molecular Modeling; v. 25, n. 9 SEP 2019.
• Web of Science Citations: 0

Abstract

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)

• FAPESP's process: 13/08166-5 - Interfacial chemistry: drugs, peptides and ezymes interactions with membrane models
• Grantee: Iolanda Midea Cuccovia
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/03204-7 - Development and application of coarse-graining force field in self-assembled systems
• Grantee: Luis Gustavo Dias
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/04176-4 - Systematic analysis in silico of the critical behavior of amyloid beta peptide and some of its mutants
• Grantee: Nelson Augusto Alves
• Support Opportunities: Regular Research Grants