کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5371071 | 1503929 | 2014 | 9 صفحه PDF | دانلود رایگان |
- H43R exhibits greater mobility at Zn-binding and electrostatic loops.
- Dimer interface interaction in H43R is weakened compared to that of WT and W32F.
- Distances between the highly conserved amino acids increase for H43R.
- The decreased activity should be attributed to the opening of active channel in H43R.
Recently, mutations in copper-zinc superoxide dismutase (SOD1) have been linked to familial amyotrophic lateral sclerosis (fALS), a progressive neurodegenerative disease involving motor neuron loss, paralysis and death. It is mainly due to protein misfolding and aggregation resulting from the enhanced peroxidase activity of SOD1 mutants. In this study, we have carried out a 20Â ns molecular dynamics simulation for wild type (WT), H43R and W32F mutated SOD1's dimer and compared their structure and conformational properties by extracting several quantitative properties from the trajectory to understand the pathology of fALS disease. Our results show considerable differences in H43R compared to WT and W32F mutated SOD1, such as increasing distances between the critical residues results in open conformation at the active site, strong fluctuations in the important loops (Zinc and electrostatic loops) and weakening of important hydrogen bonds especially between N (His 43/Arg 43) and carbonyl oxygen (His 120) in agreement with the experimental report. The calculated buried surface area of dimer interface for WT, H43R and W32F are 682, 726 and 657Â Ã 2 respectively, representing the loss of dimerization in H43R. Essential dynamics reveal that overall motions of WT and W32F are mainly involved in three to four eigenvectors, but in H43R the overall motions are mainly in the first eigenvector. These data thus provide a unifying description for the structural destabilization, enhanced peroxidase activity, loss of dismutation activity and increase in aggregation propensity in the pathology of fALS diseases.
Journal: Biophysical Chemistry - Volume 185, January 2014, Pages 70-78