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Coordination Dynamics of Zinc Triggers the Rate Determining Proton Transfer in Human Carbonic Anhydrase II
Author(s) -
Paul Tanmoy Kumar,
Taraphder Srabani
Publication year - 2020
Publication title -
chemphyschem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.016
H-Index - 140
eISSN - 1439-7641
pISSN - 1439-4235
DOI - 10.1002/cphc.202000177
Subject(s) - chemistry , deprotonation , carbonic anhydrase ii , zinc , intramolecular force , trigonal bipyramidal molecular geometry , proton , active site , molecular dynamics , molecule , reaction rate constant , coordination number , hydrogen bond , carbonic anhydrase , coordination sphere , crystallography , ion , computational chemistry , stereochemistry , kinetics , catalysis , enzyme , organic chemistry , physics , quantum mechanics
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 ask P = 1 . 29 × 1 0 6s - 1from P andk T = 4 . 37 × 1 0 4s - 1from T. A quantitative match of estimated k P with the experimental value, ( k e x p ∼ 0 . 8 × 1 0 6s - 1) suggests that dynamics of Zn coordination triggers the rate determining proton transfer step in HCA II.