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Characterisation of the Structure and Oligomerisation of Islet Amyloid Polypeptides (IAPP): A Review of Molecular Dynamics Simulation Studies

School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute and Curtin Institute for Computation, Curtin University, GPO Box U1987, Perth, WA 6845, Australia
Centre of Excellence for Alzheimer’s Disease Research and Care, School of Medical and Health Sciences, 270 Joondalup Drive, Edith Cowan University, Joondalup, WA 6027, Australia
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2018, 23(9), 2142;
Received: 8 August 2018 / Revised: 21 August 2018 / Accepted: 22 August 2018 / Published: 25 August 2018
(This article belongs to the Special Issue Molecular Simulation of Protein Structure, Dynamics and Interactions)
Human islet amyloid polypeptide (hIAPP) is a naturally occurring, intrinsically disordered protein whose abnormal aggregation into amyloid fibrils is a pathological feature in type 2 diabetes, and its cross-aggregation with amyloid beta has been linked to an increased risk of Alzheimer’s disease. The soluble, oligomeric forms of hIAPP are the most toxic to β-cells in the pancreas. However, the structure of these oligomeric forms is difficult to characterise because of their intrinsic disorder and their tendency to rapidly aggregate into insoluble fibrils. Experimental studies of hIAPP have generally used non-physiological conditions to prevent aggregation, and they have been unable to describe its soluble monomeric and oligomeric structure at physiological conditions. Molecular dynamics (MD) simulations offer an alternative for the detailed characterisation of the monomeric structure of hIAPP and its aggregation in aqueous solution. This paper reviews the knowledge that has been gained by the use of MD simulations, and its relationship to experimental data for both hIAPP and rat IAPP. In particular, the influence of the choice of force field and water models, the choice of initial structure, and the configurational sampling method used, are discussed in detail. Characterisation of the solution structure of hIAPP and its mechanism of oligomerisation is important to understanding its cellular toxicity and its role in disease states, and may ultimately offer new opportunities for therapeutic interventions. View Full-Text
Keywords: amyloidogenesis; protein aggregation; molecular simulation amyloidogenesis; protein aggregation; molecular simulation
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Moore, S.J.; Sonar, K.; Bharadwaj, P.; Deplazes, E.; Mancera, R.L. Characterisation of the Structure and Oligomerisation of Islet Amyloid Polypeptides (IAPP): A Review of Molecular Dynamics Simulation Studies. Molecules 2018, 23, 2142.

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