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.

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

Cell Biochemistry and Biophysics

Formation of protein aggregation is considered a hallmark feature of various neurological diseases. Amyotrophic lateral sclerosis is one such devastating neurodegenerative disorder characterized by mutation in Cu/Zn superoxide dismutase protein (SOD1). In our study, we contemplated the most aggregated and pathogenic mutant A4V in a viewpoint of finding a therapeutic regime by inhibiting the formation of the aggregates with the aid of tripeptides since new perspectives in the field of drug design in the current era are being focused on peptide-based drugs. Reports from the experimental study have stipulated that the SOD1 derived peptide, “LSGDHCIIGRTLVVHEKADD” was found to have the inhibitory activity against aggregated SOD1 protein. Moreover, it was determined that the hexapeptide, “LSGDHC” was the key factor in inhibiting the aggregates of SOD1. Accordingly, we utilized the computerized algorithms and programs on determining the binding efficiency and inhibitory activity of hexapeptide on mutant SOD1. Following that, we incorporated a cutting-edge methodology with the use of molecular docking, affinity predictions, alanine scanning, steered molecular dynamics (SMD) and discrete molecular dynamics (DMD) in designing the de novo tripeptides, which could act against the aggregated mutant SOD1 protein. Upon examining the results from the various conformational studies, we identified that CGH had an enhanced binding affinity and inhibitory activity against the aggregated mutant SOD1 protein than other tripeptides and hexapeptide. Thus, our study could be a lead for state-of-the-art design in peptide-based drugs for doctoring the cureless ALS disorder. © 2019 Elsevier B.V.

Journal of the Neurological Sciences

Rational design of linear tripeptides against the aggregation of human mutant SOD1 protein causing amyotrophic lateral sclerosis

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.

The Protein Journal

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

Amyotrophic lateral sclerosis (ALS) is a calamitous neurodegenerative disorder characterized by denervation of upper and lower motor neurons. Numerous hypotheses suggest that toxic protein misfolding and aggregation cause ALS, similar to that of other neurodegenerative diseases, such as Alzheimers and Parkinsons. Protruding causes of familial ALS are mutations in the gene encoding Cu/Zn superoxide dismutase-1 (SOD1), which decrease protein stability and endorse protein aggregation. Thus, the interference concerning aggregate formation and destabilization in SOD1 is considered to be an impending therapeutic strategy. In this work, we utilized computational chemistry methods to initially study the effect of substitution mutation, His46Arg on SOD1 protein. Further, we described the interaction of two naturally occurring polyphenol compounds, naringin and naringenin with mutant SOD1 that is regarded to hinder the protein aggregation. Subsequently, the use of quantum chemical and molecular mechanics calculations speculated that naringin had a strong binding affinity with mutant SOD1 and impeded the formation of toxic aggregates than that of naringenin. Ultimately, we could conjecture that ingesting of polyphenol-rich foods in ALS patients may be regarded to improvise their living. Moreover, the findings from our study could pave a way in the field of structure-based drug design in developing potential anti-aggregation inhibitors against incurable ALS, affecting the human population.

Progress in Biophysics and Molecular Biology

Molecular binding response of naringin and naringenin to H46R mutant SOD1 protein in combating protein aggregation using density functional theory and discrete molecular dynamics

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that has been associated with mutations in metalloenzyme superoxide dismutase (SOD1) causing protein structural destabilization and aggregation. However, the mechanistic action and the cure for the disease still remain obscure. Herein, we initially studied the conformational preferences of SOD1 protein structures upon substitution of Ala at Gly93 in comparison with that of wild type. Our results corroborated with the previous experimental studies on the aggregation and the destabilizing activity of mutant SOD1 protein G93A. On the therapeutic point of view, we computationally analyzed the influence of resveratrol, a natural polyphenol widely found in red wine on mutant SOD1 relative to wild type, using molecular docking studies. Further, FMO calculations were performed, using GAMESS to study the pair residual interaction on the wild type and mutant complex systems. Consequently, the resveratrol showed greater interaction with mutant than the wild type. Subsequently, we evaluated the conformational preferences of wild type and mutant complex systems, where the protein conformational structures of mutant that were earlier found to lose their conformational stability was regained, upon binding with resveratrol. Similar trend of results were found on the 2-D free energy landscapes of both the wild type and mutant systems. Hence, the combined biophysical and quantum chemical studies in our study supported the results of previous experimental studies, thereby stipulating an action of resveratrol on mutant SOD1 and paving a way for the design of highly potent effective inhibitors against fALS affecting the mankind. © 2018, Springer Nature Switzerland AG.

Journal of Computer-Aided Molecular Design

Quantum chemical and molecular mechanics studies on the assessment of interactions between resveratrol and mutant SOD1 (G93A) protein

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

Tumor Biology

Impact of point mutation P29S in RAC1 on tumorigenesis

Biophysical aspect of phosphatidylinositol 3-kinase and role of oncogenic mutants (E542K & E545K)

Curcumin inhibits the aberrant aggregation in mutant SOD1 protein, thereby decreasing the propensity of β-sheets and the toxicity level.

RSC Advances

Computational investigation of curcumin, a natural polyphenol that inhibits the destabilization and the aggregation of human SOD1 mutant (Ala4Val)

Fulltext

Role of ELA region in auto-activation of mutant KIT receptor: a molecular dynamics simulation insight

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	Data powered by TypesetCell Biochemistry and Biophysics
Publisher	Data powered by TypesetSpringer Science and Business Media LLC
ISSN	1085-9195
Open Access	No