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.
We present a review of the use of molecular dynamics techniques to study the behaviour of proteins. The application of such methods to biological macromolecules has evolved directly from its use to study simpler physical and chemical systems. We describe the methods typically used in producing multiple nanosecond atomic trajectories. This technique is now so common that it is impossible to review the whole area. Therefore, we have focused on three areas, namely the application to proteins of biomedical importance, to folding of proteins from a random conformation to a stable well-defined tertiary structure and to the reverse process, that of unfolding. Finally, we describe some methods which have been developed to analyse complex trajectories with the aim of defining the most important features of protein dynamics and changes in conformation.
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