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Simulations of Human Lysozyme: Probing the Conformations Triggering Amyloidosis

School of Crystallography, Birkbeck College, University of London, London WC1E 7HX, United Kingdom

Correspondence: Address reprint requests to Julia M. Goodfellow, School of Crystallography, Birkbeck College, University of London, Malet Street, London WC1E 7HX, UK. Tel.: 44-01793-413208; E-mail: julia.goodfellow{at}bbsrc.ac.uk.

A natural mutant of human lysozyme, D67H, causes hereditary systemic nonneuropathic amyloidosis, which can be fatal. In this disease, insoluble ß-stranded fibrils (amyloids) are found in tissues stemming from the aggregation of partially folded intermediates of the mutant. In this study, we specifically compare the conformation and properties of the structures adopted from the induced unfolding, at elevated temperature, using molecular dynamics. To increase the sampling of the unfolding conformational landscape, three 5 ns trajectories are performed for each of the wild-type and mutant D67H proteins resulting in a total of 30 ns simulation. Our results show that the mutant unfolds slightly faster than the wild-type with both wild-type and mutant proteins losing most of their native secondary structure within the first 2 ns. They both develop random transient ß-strands across the whole polypeptide chain. Clustering analysis of all the conformations shows that a high population of the mutant protein conformations have a distorted ß-domain. This is consistent with experimental results suggesting that this region is pivotal in the formation of conformations prone to act as "seeds" for amyloid fiber formation.

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