Simulations of human lysozyme: probing the conformations triggering amyloidosis.
A natural mutant of human lysozyme, D67H, causes hereditary systemic nonneuropathic amyloidosis, which can be fatal. In this disease, insoluble beta-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 beta-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 beta-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.
Moraitakis
George
G
School of Crystallography, Birkbeck College, University of London, London WC1E 7HX, United Kingdom.
Goodfellow
Julia M
JM
D028226:Amyloidosis, Familial / Q000201:enzymology* / Q000235:genetics; D003198:Computer Simulation; D003461:Crystallography / Q000379:methods*; D004789:Enzyme Activation; D004795:Enzyme Stability; D006358:Hot Temperature; D006801:Humans; D008958:Models, Molecular; D009038:Motion; D009113:Muramidase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
D011994:Recombinant Proteins; D009113:Muramidase