title: Full length amylin oligomer aggregation: insights from molecular dynamics simulations and implications for design of aggregation inhibitors.
abstract: Amyloid oligomers are considered to play essential roles in the pathogenesis of amyloid-related degenerative diseases including type 2 diabetes. Using an explicit solvent all atomic MD simulation, we explored the stability, conformational dynamics and association force of different single-layer models of the full-length wild-type and glycine mutants of amylin (pentamer) obtained from a recent high resolution fibril model. The RMSF profile shows enhanced flexibility in the disorder (Lys1-Cys7) and turn region (Ser19-Gly23), along with smallest fluctuation at the residues (Asn14-Phe15-Leu16-Val17-His18) of β1 region and (Ala25-Ile26-Leu27-Ser28-Ser29) of the β2 region. We obtained a significant difference in backbone RMSD between the wild-type and the mutants, indicating that mutations affected the stability of the peptide. The RMSD and RMSF profiles indicate the edge and loop residues are the primary contributors to the overall conformational changes. The degree of structural similarity between the oligomers in the simulation and the fibril conformation is proposed as the possible explanation for experimentally observed shortening of the nucleation lag phase of amylin with oligomer seeding. On the basis of structure-stability findings, the β1 and β2 portions are optimal target for further anti-amyloid drug design. The MM-PBSA binding energy calculation reveals the binding of amylin: amylin strands in single layer is dominated by contributions from van der Waals interactions. The non-polar solvation term is also found to be favorable. While the electrostatic interactions and polar solvation energy was found to be favorable for the interaction for the larger aggregate and unfavorable for the smaller aggregates. A per-residue decomposition of the binding free energy has been performed to identify the residues contributing most to the self-association free energy. Residues found in the β-sheet regions were found to be key residue making the largest favorable contributions to the single-layer association. The result from our simulation could be used in rational design of new amylinomimetic agent, amylin aggregation inhibitors and amylin-specific biomarkers.
authors.affiliation: a NanoScience Technology Center and Department of Chemistry , University of Central Florida , Orlando , FL , 32826 , USA .
authors.forename: Workalemahu Mikre
authors.initials: WM
authors.lastname: Berhanu
authors.forename: Artëm E
authors.initials: AE
authors.lastname: Masunov
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016000:Cluster Analysis; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D058228:Islet Amyloid Polypeptide / Q000737:chemistry*; D051379:Mice; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D066329:Protein Aggregates; D055503:Protein Multimerization; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D058228:Islet Amyloid Polypeptide; D066329:Protein Aggregates
keywords: MM-PBSA; RMSD; RMSF; amylin; cluster analysis; critical nucleation; cross seeding; free energy; lag phase; oligomer; pramlintide; secondary structure