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Journal of Molecular Modeling

, 25:263 | Cite as

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

  • Nelson A. AlvesEmail author
  • Luis G. Dias
  • Rafael B. Frigori
Original Paper
  • 84 Downloads

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\(\rightarrow \beta \)-sheets resembling hIAPP. This channel is depleted in rIAPP and is absent in sIAPP+. As a consequence, sIAPP+ presents an overall decrease of β-like secondary structures and an overstabilization of α-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.

Graphical Abstract

S20R-Pramlintide

Keywords

Amylin analogues Rational drug design Aggregation mechanisms REMD simulations Thermodynamic analysis Solvation energy Poisson-Boltzmann 

Notes

Funding information

N.A.A. gratefully acknowledges financial support from the brazilian agency FAPESP process 16/04176-4 and computer resources at the BlueGene/Q supercomputing facility through the USP-Rice collaboration. L.G.D. acknowledges financial support from the brazilian agency FAPESP processes 13/08166-5 and 17/03204-7. R.B.F. thanks the Brazilian National Laboratory for Scientific Computing (LNCC) by supercomputing resources granted at the Santos Dumont facility under project PHAST2.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Departamento de Física, FFCLRPUniversidade de São PauloRibeirão PretoBrazil
  2. 2.Departamento de Química, FFCLRPUniversidade de São PauloRibeirão PretoBrazil
  3. 3.Universidade Tecnológica Federal do ParanáToledoBrazil

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