Structural investigation on the electrostatic loop of native and mutated SOD1 and their interaction with therapeutic compounds

Abstract

A β-sheet cytosolic enzymatic protein, [Cu–Zn superoxide dismutase 1, (Cu–Zn SOD1)] not only neutralizes superoxide radicals but also catalyses their disproportionation into hydrogen peroxide and molecular oxygen. The structure and activity of the SOD1 protein depend on two important loops, viz. Zn-binding and an electrostatic loop [E-loop]. In this work, the electrostatic loop of the SOD1 protein in the native and mutated states with single point mutation in the loop, viz. D124V, D125H and S134N, is subjected to molecular dynamics simulation for a period of 50 000 ps. The mutated E-loops are docked with four different chemical compounds, viz. 5-fluorouridine, isoproteranol, 4-(4-methyl-1,4-diazepan-1-yl)-2-(trifluromethyl) quinazoline and uridine-5-monophosphate. The structures with larger binding affinity are again subjected to molecular dynamics simulation for a period of 50 000 ps. The structure and electrostatic properties of the mutated E-loops before and after interacting with the chemical compounds are compared with those of the E-loop in the native state. It is found that the chemical compounds reduce the effect of the E-loop in the mutated SOD1 proteins by reorienting the mutated E-loop in such a way that it exhibits structural and electrostatic properties close to those of the E-loop in the native state. Among the different chemical compounds of interest, uridine-5-monophosphate is found to exhibit better interaction, which helps to reduce the rapid aggregation of the SOD1 protein due to Familial Amyotrophic Lateral Sclerosis [FALS] mutations. Molecular dynamics simulation for the mutated E-loops generates an ensemble of configurations, and the conformational sampling in these configurations is examined using the free energy profile.