Biophys Chem 1998 Dec 14;753:235-48. doi: 10.1016/s0301-4622(98)00209-9.

A spectroscopic and molecular dynamics study of native and of a mutant of Xenopus laevis Cu,Zn superoxide dismutase: mechanistic consequences of replacing four charged amino acids on the 'electrostatic' loop.

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Neutralisation by site-directed mutagenesis of four charged and highly conserved residues of the electrostatic loop of Cu,Zn superoxide dismutase from Xenopus laevis, involved in the electrostatic attraction of the substrate: Lys120-->Leu, Asp130-->Gln, Glu131-->Gln and Lys134-->Thr, gives rise to a mutant enzyme which displays an affinity for monovalent inhibitor anions, such as N3-, higher than that of the wild type. Analysis of 300 ps of molecular dynamics simulation carried out on the wild type and on the Xenopus laevis Cu,Zn superoxide dismutase mutant indicates that the two proteins display a distinct dynamical behaviour. In particular the root mean square deviation from the starting structure, the number of residues in random coil conformations, the number of residues in unfavourable regions of the Ramachandran plot indicate that the mutant displays a rigidity higher than the native enzyme. This is also evidenced by the loss of dynamical cross correlations in the simulation of the mutant, which on the other hand are present in the wild type. Moreover the mutant protein shows a different organisation of the backbone-to-backbone hydrogen bonds network that generates a rigid structure leading to an increase of the active site accessibility when compared to the native enzyme. It is suggested that the rigid state in which the mutant is confined, accompanied by the increase of the solvent accessible surface of the active site may explain the difference in reactivity toward the inhibitor anion.

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