Active Species for the Ground-State Complex of Cytidine Deaminase:  A Linear-Scaling Quantum Mechanical Investigation

We present results of large-scale (1330 atoms) linear-scaling quantum mechanical semiempirical (PM3) simulations done to optimize geometries surrounding the active site within the enzyme cytidine deaminase. We make a strong prediction about the structure of the active site for the active species, based on the energetics of the calculated structures and comparisons to X-ray crystallographic data. The lowest energy structure indicates that Zn−OH - is the active species formed prior to nucleophilic attack of the ligand, that the active species of Glu-104 is with O ε 2 protonated and hydrogen-bonded with N 3 of the ligand, and that the C 4 and OH - atoms are significantly closer than is permitted by their van der Waals radii. In addition, we predict structures corresponding to the low-pH and high-pH states in the active site of the enzyme.