Binding of bicarbonate to human carbonic anhydrase II: A continuum of binding states

Herein, we report molecular dynamics simulations of the enzyme human carbonic anhydrase II (HCAII) complexed with the substrate molecule bicarbonate using a quantum mechanical/molecular mechanical (QM/MM) coupled potential. This study provides novel insights into bicarbonate binding and loss: In particular, we find that a structure related to the so-called Lipscomb binding motif is the global minimum, while the first formed Lindskog binding mode is unstable relative to alternative binding modes. From our simulated results we are able to postulate why Thr-199 destabilizes bicarbonate binding to HCAII (relative to the Ala-199 mutant) and how bicarbonate ion is displace by water to form the zinc-water form of HCAII. This study also demonstrates the capability of QM/MM methods to elucidate structural and mechanistic aspects of enzyme mechanisms.