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Research Article

Solvent sensitivity of protein aggregation in Cu, Zn superoxide dismutase: a molecular dynamics simulation study

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Pages 2605-2617 | Received 12 Jun 2017, Accepted 01 Aug 2017, Published online: 20 Aug 2017
 

Abstract

Misfolding and aggregation of Cu, Zn Superoxide Dismutase (SOD1) is often found in amyotrophic lateral sclerosis (ALS) patients. The central apo SOD1 barrel was involved in protein maturation and pathological aggregation in ALS. In this work, we employed atomistic molecular dynamics (MD) simulations to study the conformational dynamics of SOD1barrel monomer in different concentrations of trifluoroethanol (TFE). We find concentration dependence unusual structural and dynamical features, characterized by the local unfolding of SOD1barrel. This partially unfolded structure is characterized by the exposure of hydrophobic core, is highly dynamic in nature, and is the precursor of aggregation seen in SOD1barrel. Our computational studies supports the hypothesis of the formation of aggregation ‘building blocks’ by means of local unfolding of apo monomer as the mechanism of SOD1 fibrillar aggregation. The non-monotonic TFE concentration dependence of protein conformational changes was explored through simulation studies. Our results suggest that altered protein conformation and dynamics within its structure may underlie the aggregation of SOD1 in ALS.

Acknowledgements

A.P. and V.K. sincerely thank Science and Engineering Research Board (SERB), Government of India for the award of Young Scientist, YSS/2015/000228 and SB/YS/LS-161/2014, respectively. Authors sincerely thank DST-SERB for providing the GPU computational Facility.

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