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

TLDR: The study postulated a classical treatment against mutant SOD1, using the naturally occurring polyphenol (curcumin) via the computational framework for designing therapeutics against ALS, and suggested that curcumin showed an enhanced binding affinity in the mutant Sod1 with increased hydrophobic interactions as compared to native S OD1.

Abstract: Aberrant aggregation in proteins leads to increased propensity of β-sheets, thereby increasing the toxicity level Numerous neurological disorders are triggered due to aggregation in protein Superoxide dismutase 1 (SOD1) is one such protein that leads to familial amyotrophic lateral sclerosis, a devastating neurodegenerative disorder In our study, the aggregation effect in native and the fatal mutant (Ala4Val) SOD1 was examined, using tCONCOORD Experimental studies reported that the naturally obtained polyphenol has an inhibitory effect on the aggregated protein Consequently, we predominantly focused on curcumin, a natural occurring polyphenol, to inhibit the aggregation in SOD1 In view of that, curcumin was computationally docked with both the native and mutant SOD1, using Autodock Thus, our analysis suggested that curcumin showed an enhanced binding affinity in the mutant SOD1 with increased hydrophobic interactions as compared to native SOD1 Further investigations were accomplished, using steered molecular dynamics and conformational sampling on both the bound complexes of native and mutant SOD1 with curcumin to unravel the effect of disaggregation In addition, we also elucidated the variations in the free energy landscape of native and mutant SOD1 in their unbound and bound states to differentiate the aggregation Hence, the study postulated a classical treatment against mutant SOD1, using the naturally occurring polyphenol (curcumin) via the computational framework for designing therapeutics against ALS