Coordination Dynamics of Zinc Triggers the Rate Determining Proton Transfer in Human Carbonic Anhydrase II. Issue 13 (2nd June 2020)

• Record Type: Journal Article
• Authors: Paul, Tanmoy Kumar; Taraphder, Srabani
• Is Part Of: Chemphyschem. Volume 21:Issue 13(2020)
• Page Start: 1455
• Page End: 1473
• Publication Date: 2020-06-02
• Subjects: Carbonic anhydrase -- coordination dynamics -- proton transfer -- transition path sampling -- zinc; Chemistry, Physical and theoretical -- Periodicals; 541.05
• DOI: 10.1002/cphc.202000177
• Languages: English
• ISSNs: 1439-4235

Abstract

Abstract: We present, for the first time, how transient changes in the coordination number of zinc ion affects the rate determining step in the enzyme human carbonic anhydrase (HCA) II. The latter involves an intramolecular proton transfer between a zinc‐bound water and a distant histidine residue (His‐64). In the absence of time‐resolved experiments, results from classical and QM‐MM molecular dynamics and transition path sampling simulations are presented. The catalytic zinc ion is found to be present in two possible coordination states; viz. a stable tetra‐coordinated state, T and a less stable penta‐coordinated state, P with tetrahedral and trigonal bipyramidal coordination geometries, respectively. A fast dynamical inter‐conversion occurs between T and P due to reorganization of active site water molecules making the zinc ion more positively charged in state P. When initiated from different coordination environments, the most probable mechanism of proton transfer is found to be deprotonation of the equatorial water molecule from state P and transfer of the excess proton via a short path formed by hydrogen bonded network of active site water molecules. We estimate the rate constant of proton transfer as k P = 1 . 29 × 1 0 6 s - 1 from P and k T = 4 . 37 × 1 0 4 s - 1 from T. A quantitative match of estimated kP with the experimental value, ( k e x p ∼ 0 . 8 × 1 0 6 s - 1 ) suggests that dynamics of Zn coordination triggers the rate determining proton transfer step in HCA II. Abstract : The kinetics of rate determining proton transfer reaction in the enzyme human carbonic anhydrase (HCA) II is reported using advanced computer simulation studies. In addition to a stable tetra‐coordinated state, the catalytic zinc ion at the active site of HCA II is found to populate a transient penta‐coordinated state by binding to an extra water molecule. This transient state facilitates a preferential deprotonation of the equatorial water molecule bonded to zinc and formation of a short path for a facile proton transfer with a correct rate constant.