PMID- 19679196
OWN - NLM
STAT- MEDLINE
DCOM- 20100401
LR  - 20211020
IS  - 0006-3002 (Print)
IS  - 1878-2434 (Electronic)
IS  - 0006-3002 (Linking)
VI  - 1804
IP  - 2
DP  - 2010 Feb
TI  - Proton transfer function of carbonic anhydrase: Insights from QM/MM simulations.
PG  - 342-51
LID - 10.1016/j.bbapap.2009.07.026 [doi]
AB  - Recent QM/MM analyses of proton transfer function of human carbonic anhydrase II 
      (CAII) are briefly reviewed. The topics include a preliminary analysis of nuclear 
      quadrupole coupling constant calculations for the zinc ion and more detailed 
      analyses of microscopic pK(a) of the zinc-bound water and free energy profile for 
      the proton transfer. From a methodological perspective, our results emphasize 
      that performing sufficient sampling is essential to the calculation of all these 
      quantities, which reflects the well solvated nature of CAII active site. From a 
      mechanistic perspective, our analyses highlight the importance of electrostatics 
      in shaping the energetics and kinetics of proton transfer in CAII for its 
      function. We argue that once the pK(a) for the zinc-bound water is modulated to 
      be in the proper range (approximately 7.0), proton transfer through a relatively 
      well solvated cavity towards/from the protein surface (His64) does not require 
      any major acceleration. Therefore, although structural details like the length of 
      the water wire between the donor and acceptor groups still may make a 
      non-negligible contribution, our computational results and the framework of 
      analysis suggest that the significance of such "fine-tuning" is likely secondary 
      to the modulation of pK(a) of the zinc-bound water. We encourage further 
      experimental analysis with mutation of (charged) residues not in the immediate 
      neighborhood of the zinc ion to quantitatively test this electrostatics based 
      framework; in particular, Phi analysis based on these mutations may shed further 
      light into the relative importance of the classical Grotthus mechanism and the 
      "proton hole" pathway that we have proposed recently for CAII.
CI  - Copyright 2009 Elsevier B.V. All rights reserved.
FAU - Riccardi, Demian
AU  - Riccardi D
AD  - Department of Biochemistry, University of Wisconsin, Madison, Madison, WI 53706, 
      USA.
FAU - Yang, Shuo
AU  - Yang S
FAU - Cui, Qiang
AU  - Cui Q
LA  - eng
GR  - R01 GM071428/GM/NIGMS NIH HHS/United States
GR  - R01-GM71428/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Review
DEP - 20090811
PL  - Netherlands
TA  - Biochim Biophys Acta
JT  - Biochimica et biophysica acta
JID - 0217513
RN  - 0 (Protons)
RN  - 059QF0KO0R (Water)
RN  - EC 4.2.1.1 (Carbonic Anhydrases)
SB  - IM
MH  - Animals
MH  - Carbonic Anhydrases/*chemistry/*metabolism
MH  - *Computer Simulation
MH  - Humans
MH  - Ion Transport
MH  - *Protons
MH  - Quantum Dots
MH  - Water
PMC - PMC6787916
MID - NIHMS1053854
EDAT- 2009/08/15 09:00
MHDA- 2010/04/02 06:00
PMCR- 2019/10/11
CRDT- 2009/08/15 09:00
PHST- 2009/07/01 00:00 [received]
PHST- 2009/07/24 00:00 [revised]
PHST- 2009/07/29 00:00 [accepted]
PHST- 2009/08/15 09:00 [entrez]
PHST- 2009/08/15 09:00 [pubmed]
PHST- 2010/04/02 06:00 [medline]
PHST- 2019/10/11 00:00 [pmc-release]
AID - S1570-9639(09)00194-0 [pii]
AID - 10.1016/j.bbapap.2009.07.026 [doi]
PST - ppublish
SO  - Biochim Biophys Acta. 2010 Feb;1804(2):342-51. doi: 10.1016/j.bbapap.2009.07.026. 
      Epub 2009 Aug 11.