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.