Molecular dynamics simulation of substrate-enzyme interactions in the active site channel of superoxide dismutase

Abstract Molecular dynamics simulations of the diffusion of superoxide ion down the active site channel of the enzyme superoxide dismutase were performed with a parallelized version of GROMOS on the Intel iPSC/860. Our model consisted of a spherical assembly of 6968 atoms centered at a copper ion in the enzyme. Trajectory analysis revealed that the anion is directed toward the copper ion through the cooperative motions of several active site residues. Other mechanistic and structural motifs recurring through five full trajectories are examined. In addition to these qualitative results, an upper bound has been calculated for the rate constant for displacement by substrate of the water molecule that is coordinated to the copper. This required an analysis of the dynamics of crossing a free energy barrier that has been characterized in previous work. Strong frictional effects due to Coulombic interactions lead to a rather small rate constant; the transmission coefficient is less than 0.01. The mechanism of th...

[1]  J. Mccammon,et al.  Point charge distributions and electrostatic steering in enzyme/substrate encounter: Brownian dynamics of modified copper/zinc superoxide dismutases. , 1990, Biochemistry.

[2]  I. Ghosh,et al.  Sidechain rotational isomerization in proteins. Dynamic simulation with solvent surroundings. , 1987, Biophysical journal.

[3]  J. Richardson,et al.  Determination and analysis of the 2 A-structure of copper, zinc superoxide dismutase. , 1980, Journal of molecular biology.

[4]  J. V. Bannister,et al.  The superoxide dismutase activity of human erythrocuprein , 1973, FEBS letters.

[5]  D. T. Sawyer,et al.  Potentiometric titrations and oxidation-reduction potentials of manganese and copper-zinc superoxide dismutases. , 1979, Biochemistry.

[6]  Peter A. Kollman,et al.  Electrostatic recognition between superoxide and copper, zinc superoxide dismutase , 1983, Nature.

[7]  John A. Tainer,et al.  Structure and mechanism of copper, zinc superoxide dismutase , 1983, Nature.

[8]  R. Osman,et al.  On the mechanism of action of superoxide dismutase: a theoretical study , 1984 .

[9]  S. H. Koenig,et al.  Nuclear magnetic relaxation dispersion in protein solutions. V. Bovine erythrocyte superoxide dismutase. , 1972, Biochimica et biophysica acta.

[10]  I. Bertini,et al.  The electron-nucleus dipolar coupling in slow rotating systems. 2. The effect of g anisotropy and hyperfine coupling when S = 12 and I = 32 , 1985 .

[11]  I. Fridovich,et al.  Examination of the role of arginine-143 in the human copper and zinc superoxide dismutase by site-specific mutagenesis. , 1987, The Journal of biological chemistry.

[12]  James Andrew McCammon,et al.  Parallel Molecular Dynamics , 1991, PPSC.

[13]  E. Getzoff,et al.  Faster superoxide dismutase mutants designed by enhancing electrostatic guidance , 1992, Nature.

[14]  J. Mccammon,et al.  Dynamics of Proteins and Nucleic Acids , 2018 .

[15]  G. Rotilio,et al.  A pulse radiolysis study of superoxide dismutase. , 1972, Biochimica et biophysica acta.

[16]  I. Bertini,et al.  An investigation of a human erythrocyte SOD modified at position 137 , 1989 .

[17]  B. Berne,et al.  On determining reaction kinetics by molecular dynamics using absorbing barriers , 1985 .

[18]  P. Viglino,et al.  Competitive inhibition of Cu, Zn superoxide dismutase by monovalent anions. , 1977, Biochemical and biophysical research communications.

[19]  S. Lippard,et al.  A pH-dependent superoxide dismutase activity for zinc-free bovine erythrocuprein. Reexamination of the role of zinc in the holoprotein. , 1982, Journal of inorganic biochemistry.

[20]  B Honig,et al.  Computer simulations of the diffusion of a substrate to an active site of an enzyme. , 1987, Science.

[21]  J. Mccammon,et al.  Molecular dynamics simulation of superoxide interacting with superoxide dismutase , 1991 .

[22]  Simulation of bimolecular reactions: synthesis of the encounter and reaction steps , 1993 .

[23]  J. Tainer,et al.  Evolution of CuZn superoxide dismutase and the Greek Key β‐barrel structural motif , 1989, Proteins.

[24]  I. Bertini,et al.  Water in the active cavity of copper/zinc superoxide dismutase. A water 1H-nuclear-magnetic-relaxation-dispersion study. , 1989, European journal of biochemistry.

[25]  Benoît Roux,et al.  Ion transport in a gramicidin-like channel: dynamics and mobility , 1991 .

[26]  I. Fridovich.  Superoxide dismutases: an adaptation to a paramagnetic gas , 1989 .

[27]  D. Case,et al.  Dynamic Simulations of Oxygen Binding to Myoglobin , 1986, Annals of the New York Academy of Sciences.