title: Nanostructure and stability of calcitonin amyloids.
abstract: Calcitonin is a 32-amino acid thyroid hormone that can form amyloid fibrils. The structural basis of the fibril formation and stabilization is still debated and poorly understood. The reason is that NMR data strongly suggest antiparallel β-sheet calcitonin assembly, whereas modeling studies on the short DFNKF peptide (corresponding to the sequence from Asp15to Phe19of human calcitonin and reported as the minimal amyloidogenic module) show that it assembles with parallel β-sheets. In this work, we first predict the structure of human calcitonin through two complementary molecular dynamics (MD) methods, finding that human calcitonin forms an α-helix. We use extensive MD simulations to compare previously proposed calcitonin fibril structures. We find that two conformations, the parallel arrangement and one of the possible antiparallel structures (with Asp15and Phe19aligned), are highly stable and ordered. Nonetheless, fibrils with parallel molecules show bulky loops formed by residues 1 to 7 located on the same side, which could limit or prevent the formation of larger amyloids. We investigate fibrils formed by the DFNKF peptide by simulating different arrangements of this amyloidogenic core sequence. We show that DFNKF fibrils are highly stable when assembled in parallel β-sheets, whereas they quickly unfold in antiparallel conformation. Our results indicate that the DFNKF peptide represents only partially the full-length calcitonin behavior. Contrary to the full-length polypeptide, in fact, the DFNKF sequence is not stable in antiparallel conformation, suggesting that the residue flanking the amyloidogenic peptide contributes to the stabilization of the experimentally observed antiparallel β-sheet packing.
authors.affiliation: From the Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Rigoldi
authors.affiliation: the Dipartimento di Chimica, Materiali e Ingegneria Chimica "Giulio Natta," Politecnico di Milano, Via L. Mancinelli 7, 20131 Milano, Italy, and.|the VTT - Tecnical Research Centre of Finland, Biologinkuja 7, 02150 Espoo, Finland.
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Metrangolo
authors.affiliation: From the Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Redaelli
authors.affiliation: From the Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano, Italy, alfonso.gautieri@polimi.it.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Gautieri
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D002116:Calcitonin / Q000737:chemistry*; D006801:Humans; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry*; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary
chemical_list: D000682:Amyloid; D010455:Peptides; D002116:Calcitonin
keywords: aggregation; amyloid; molecular dynamics; protein misfolding; protein-protein interaction