Quantum chemical and molecular mechanics studies on the assessment of interactions between resveratrol and mutant SOD1 (G93A) protein
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.
KeywordsALS SOD1 DMD Resveratrol Docking FMO
The authors thank VIT University for providing ‘VIT SEED GRANT’ for carrying out this research work.
Compliance with ethical standards
Conflict of interest
The authors declare that there are no conflicts of interest.
- 1.Redler RL, Dokholyan NV (2012) The complex molecular biology of amyotrophic lateral sclerosis (ALS). Prog Mol Biol Transl Sci 107:215–262. https://doi.org/10.1016/B978-0-12-385883-2.00002-3 CrossRefGoogle Scholar
- 6.Kato S, Takikawa M, Nakashima K et al (2000) New consensus research on neuropathological aspects of familial amyotrophic lateral sclerosis with superoxide dismutase 1 (SOD1) gene mutations: inclusions containing SOD1 in neurons and astrocytes. Amyotroph Lateral Scler Mot Neuron Disord Off Publ World Fed Neurol Res Group Mot Neuron Dis 1:163–184CrossRefGoogle Scholar
- 13.Srinivasan E, Rajasekaran R (2016) Computational simulation analysis on human SOD1 mutant (H80R) exposes the structural destabilization and the deviation of Zn binding that directs familial amyotrophic lateral sclerosis. J Biomol Struct Dyn. https://doi.org/10.1080/07391102.2016.1227723 CrossRefGoogle Scholar
- 20.Srinivasan E, Rajasekaran R (2017) 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. Cell Biochem Biophys. https://doi.org/10.1007/s12013-017-0830-5 CrossRefGoogle Scholar
- 22.Achilli F, Boyle S, Kieran D et al (2005) The SOD1 transgene in the G93A mouse model of amyotrophic lateral sclerosis lies on distal mouse chromosome 12. Amyotroph Lateral Scler Mot Neuron Disord Off Publ World Fed Neurol Res Group Mot Neuron Dis 6:111–114. https://doi.org/10.1080/14660820510035351 CrossRefGoogle Scholar
- 26.Shipp EL, Cantini F, Bertini I et al (2003) Dynamic properties of the G93A mutant of copper—zinc superoxide dismutase as detected by NMR spectroscopy: implications for the pathology of familial amyotrophic lateral sclerosis. Biochemistry 42:1890–1899. https://doi.org/10.1021/bi026704y CrossRefGoogle Scholar
- 37.Vidavalur R, Otani H, Singal PK, Maulik N (2006) Significance of wine and resveratrol in cardiovascular disease: French paradox revisited. Exp Clin Cardiol 11:217–225Google Scholar
- 38.Potter KA, Buck AC, Self WK et al (2013) The effect of resveratrol on neurodegeneration and blood brain barrier stability surrounding intracortical microelectrodes. Biomaterials 34:7001–7015. https://doi.org/10.1016/j.biomaterials.2013.05.035 CrossRefGoogle Scholar