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

• Published in: Journal of molecular modeling Vol. 25; no. 9; pp. 263 - 11
• Main Authors: Alves, Nelson A., Dias, Luis G., Frigori, Rafael B.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-09-2019; Springer Nature B.V
• Subjects: Agglomeration; Analogs; Animals; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Free energy; Helices; Humans; Islet Amyloid Polypeptide - chemistry; Islet Amyloid Polypeptide - genetics; Islet Amyloid Polypeptide - metabolism; Molecular dynamics; Molecular Dynamics Simulation; Molecular Medicine; Mutation; Original Paper; Peptides; Proline; Protein Aggregation, Pathological; Protein Structure, Secondary; Rats; Solvation; Theoretical and Computational Chemistry; Water - chemistry; Amylin analogues; Aggregation mechanisms; Solvation energy; Thermodynamic analysis; Poisson-Boltzmann; REMD simulations; Rational drug design
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-019-4137-x

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
→
β
-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