AbstractWe used Brownian dynamics simulations of substrate O 2−encounters with the enzyme bovine erythrocyte Cu, Zn superoxide dismutase (SOD) to study the effects of multiple charge modifications in the enzyme on the kinetics of its diffusion‐controlled reaction. When the charges of two or three residues were changed, the calculated rate consant relative to that for the unmodified enzyme was usually found to be the product of relative rate constants for the enzymes with the corresponding single‐site changes. This “multiplicativity” rule may be useful in the design of enzymes that operate with diffusion‐controlled kinetics. Residues that deviate from the general rule are found in the active site channel of SOD, and the origin of these deviations