Keywords: β-Sheet Stability, Amylin, Amyloid, Iapp Polypeptide, Molecular Dynamics, Neurodegenerative Diseases, Type Ii Diabetes, Amino Acid Sequence, Article, Beta Sheet, Complex Formation, Conformational Transition, Crystal Structure, Disease Association, Molecular Model, Protein Aggregation, Protein Assembly, Protein Interaction, Protein Polymorphism, Protein Transport, Crystallization, Diabetes Mellitus, Molecular Dynamics Simulation, Phenotype, Protein Conformation, Protein Structure, Secondary,
Affiliations: *** IBB - CNR ***
Istituto di Biostrutture e Bioimmagini, CNR via Mezzocannone 16, I-80134 Napoli, Italy
Dipartimento delle Scienze Biologiche, Università degli Studi di Napoli Federico II, Via Mezzocannone 16, I-80134 Napoli, Italy
Division of Molecular Biosciences, Imperial College South Kensington Campus, London SW7 2AZ, United Kingdom
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Dynamical Properties of Steric Zipper Polymorphs Formed by a IAPP-Derived Peptide
Understanding the molecular basis of neurodegenerative diseases has enormous implications for the development of effective therapeutic strategies. One of the most puzzling features of these pathologies is the occurrence of distinct strains, which are believed to be generated by alternative conformational transitions of the same protein/peptide. Very recently, it has been discovered that small model peptides are able to form alternative tightly packed assemblies (polymorphs) in the crystalline state. Intriguingly, it has been postulated that the different polymorphs of the same polypeptide sequence may be representative of distinct strains. As the organization of crystalline aggregates of small peptides may be heavily biased by crystal packing, we have here performed MD simulations on steric zipper polymorphs formed by of the IAPP-derived fragment SSTNVG. Our analyses show that these aggregates are rather stable also in a non-crystalline environment. This finding corroborates the hypothesis that steric zipper assemblies are good candidates to account for the phenomenon of strain in neurodegenerative diseases. Present investigations also provide clues on the factors that favour the formation of polymorphs. Indeed, the intrinsic stability of individual beta-sheets formed by SSTNVG strands is very poor. Therefore, the formation of these aggregates is essentially dictated by inter-sheet interactions established within the steric zipper assembly.
Dynamical Properties of Steric Zipper Polymorphs Formed by a IAPP-Derived Peptide