Mutations in the gene encoding Cu/Zn Superoxide Dismutase 1 (SOD1) protein are contemplated to be a protruding reason for Amyotrophic lateral sclerosis (ALS), which leads towards protein aggregation, misfolding and destabilization. Thus, we investigated the systematic action of entire mutations reported on electrostatic loop of SOD1 protein through thermodynamical and discrete molecular dynamics (DMD) studies. Accordingly, we analyzed the outcomes distinctly for screening the mutant structures having both, deleterious and destabilizing effect. Progressively, the impacts of those mutations on SOD1 were studied using DMD program. Surprisingly, our results predicted that the mutants viz., L126S, N139H and G141A to be the most destabilizing, misfolded and disease-causing compared to other mutants. Besides, the outcomes from secondary structural propensities and free energy landscapes, together assertively suggested that L126S, N139H and G141A tend to increase the formation of aggregates in SOD1 relative to other mutants. Hence, this study could provide an insight into the sprouting neurodegenerative disorder distressing the humans. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Rajasekaran R

Department of Biotechnology

School of Bio Sciences and Technology

Vellore Campus

Srinivasan E

Vellore Institute of Technology (VIT) is a private university located in&nbsp;Tamil Nadu, India. Founded in 1984, as Vellore Engineering College, the institution offers 20 undergraduate, 34 postgraduate, four integrated and four research programs. It has campuses in Vellore, Amravati, Bhopal and Chennai.

VIT is one of the top ranked private universities in India according to NIRF, THE and QS Rankings.&nbsp;Govt. of India has recognized&nbsp;VIT, Vellore as an&nbsp;Institution of Eminence. This has allowed VIT to take independent quality initiatives and move up in world ranking.

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VIT University

The Protein Journal

Mutations in Cu/Zn superoxide dismutase 1 (SOD1) protein are found to be the causative factor, behind the majority of familial amyotrophic later sclerosis (FALS) cases. The mutations particularly on the metal (Zn) binding residues are found to increase the disease onset in the individuals suffering from FALS, while the presence of the metal ion (Zn) is essential for the catalytic activity and retaining the protein stability. Thus in our study, we focused on one such metal binding mutant (D83G) and assessed the impact of the mutation on protein structure and function. The influence of mutation was examined dynamically, using discrete molecular dynamics on both the native and mutant SOD1 protein respectively. Accordingly, the variation in conformational stability, residual flexibility and protein compactness along with the change in conformational free energy were monitored over the entire dynamic period. Moreover, the motion of native and mutant SOD1 was also observed via the essential dynamics. Besides, the disparity in Zn ion binding was inspected through distance analysis and steered molecular dynamics, correspondingly. Therefore, the study provides a better understanding over the profound effect of mutation on SOD1, both structurally and functionally, using computational approaches. © 2017 Elsevier B.V.

International Journal of Biological Macromolecules

Deciphering the loss of metal binding due to mutation D83G of human SOD1 protein causing FALS disease

Protein aggregation is a hallmark of various neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS) in humans. Mutations in Cu/Zn superoxide dismutase (SOD1) protein were found to be a prominent cause behind the majority of the familial ALS cases with abnormal protein aggregates. Herein, we report the biophysical characterization of the beneficial mutation C111S that stabilizes the SOD1 harboring A4V mutation, one of the most lethal diseases causing mutant that leads to protein destabilization and aggregation. In this study, we utilized discrete molecular dynamics (DMD) simulations, which stipulated an outlook over the systematic action of C111S mutation in the A4V mutant that stabilizes the protein and impedes the formation of protein aggregation. Herewith, the findings from our study manifested that the mutation of C111S in SOD1 could aid in regaining the protein structural conformations that protect against the formation of toxic aggregates, thereby hindering the disease pathogenicity subtly. Hence, our study provides a feasible pharmaceutical strategy in developing the treatment for incurable ALS affecting the mankind. © 2017, Springer Science+Business Media, LLC.

Cell Biochemistry and Biophysics

Cysteine to Serine Conversion at 111th Position Renders the Disaggregation and Retains the Stabilization of Detrimental SOD1 A4V Mutant Against Amyotrophic Lateral Sclerosis in Human—A Discrete Molecular Dynamics Study

Journal of Biomolecular Structure and Dynamics

Computational simulation analysis on human SOD1 mutant (H80R) exposes the structural destabilization and the deviation of Zn binding that directs familial amyotrophic lateral sclerosis

Amyloid formation and protein aggregation are considered to be at the core of the disease pathology for the various neurodegenerative disorders such as Amyotrophic lateral sclerosis (ALS). Considerable experimental reports have suggested that epigallocatechin-gallate (EGCG), a natural polyphenol from the green tea inhibits the amyloid formation in multiple neurodegenerative disease. Mutations in SOD1 protein are considered to a key factor that contributes towards the rapid disease progression and the pathogenesis in both, the sporadic and familial form. In our study, we computationally examined the inhibitory action of EGCG against the native and the mutant SOD1 through molecular docking, steered molecular dynamics and conformational sampling methods From the outcome, we could conjecture that the protein destabilization and increased β-sheet propensity that occurred due to mutation were regained upon the binding of EGCG. Moreover, the concepts of the free energy landscape analysis are introduced to establish the visual appearance of protein aggregation upon mutation. Altogether, we come to know that the binding of EGCG on mutant SOD1 has reduced the formation of the toxic aggregates upon mutation. Hence, our study could be an initiative in deciphering the inhibitory action of EGCG against the aggregated mutant SOD1, which could be a therapeutic potential against the treatment for the incurable neurodegenerative disorder (ALS) affecting the mankind. © 2017 Elsevier Inc.

Journal of Molecular Graphics and Modelling

Probing the inhibitory activity of epigallocatechin-gallate on toxic aggregates of mutant (L84F) SOD1 protein through geometry based sampling and steered molecular dynamics

Mutations in Cu/Zn superoxide dismutase 1 (SOD1) protein are a major cause of the devastating neurodegenerative disorder Amyotrophic lateral sclerosis. Evidence suggests that SOD1 functions as a free radical scavenger in humans. However, neither the mechanism nor a cure for this neurodegenerative disease are yet known. In the present study, we explored the effect of mutations on the mechanistic action on the Zn binding loop of SOD1 through discrete molecular dynamics. The results were analyzed in detail using statistical potential (BACH) to find the mutant structures having the least potential energy. Subsequently, we studied the impact of those mutations on metal ions bound in SOD1 using the program Check My Metal. Remarkably, our results recognized certain mutants, viz. His80Arg and Asp83Gly, that were more damaging to the Zn binding loop than all other mutants, leading to a loss of Zn binding with altered coordination of the Zn ion. Furthermore, the conformational stability, compactness, and secondary structural alteration of the His80Arg and Asp83Gly mutants were monitored using distinct parameters. Hence, at low computational expense, our study provides helpful insight into this emergent neurodegenerative disorder affecting mankind. © 2017, Springer-Verlag Berlin Heidelberg.

Journal of Molecular Modeling

A theoretical study on Zn binding loop mutants instigating destabilization and metal binding loss in human SOD1 protein

Computational Investigation on Electrostatic Loop Mutants Instigating Destabilization and Aggregation on Human SOD1 Protein Causing Amyotrophic Lateral Sclerosis

Journal	Data powered by TypesetThe Protein Journal
Publisher	Data powered by TypesetSpringer Science and Business Media LLC
ISSN	1572-3887
Open Access	No