PMID- 18247480
OWN - NLM
STAT- MEDLINE
DCOM- 20080506
LR  - 20131121
IS  - 0006-2960 (Print)
IS  - 0006-2960 (Linking)
VI  - 47
IP  - 8
DP  - 2008 Feb 26
TI  - Proton transfer in carbonic anhydrase is controlled by electrostatics rather than 
      the orientation of the acceptor.
PG  - 2369-78
LID - 10.1021/bi701950j [doi]
AB  - Combined quantum mechanical/molecular mechanical (QM/MM) simulations are carried 
      out to analyze factors that dictate the proton transfer in carbonic anhydrase II 
      (CAII), an enzyme that has been used as a prototypical example of long-range 
      proton transfers in biomolecules. In contrast to the long-held conjecture in the 
      experimental literature, the computed potentials of mean force (PMF) suggest that 
      the proton transfer in CAII is not very sensitive to the orientation of the 
      acceptor group (His 64) and, therefore, the number of water molecules that bridge 
      the donor (zinc-water) and acceptor groups. Perturbative analysis indicates that 
      a series of polar and charged residues close to the transfer pathways make the 
      dominant contribution to the barrier and exothermicity of the proton transfer 
      reaction, thus supporting the proposal from previous studies of Warshel and 
      co-workers using a somewhat simpler QM/MM model that electrostatic interactions 
      play a major role in the proton transfer in CAII. The PMF results are in striking 
      contrast to previous analysis using the same QM/MM method but an ensemble of 
      minimum energy path (MEP) calculations, which found a steep dependence of the 
      barrier height on the number of bridging water molecules. Analysis of the 
      configurations sampled in the PMF and MEP simulations suggests that this 
      difference arises because the PMF simulations sample a largely stepwise mechanism 
      while the local MEP calculations artificially favored concerted transfers due to 
      the specific protocol used to generate the initial configurations. Therefore, 
      this study presents a compelling argument for carrying out proper conformational 
      sampling in the study of long-range proton transfers. Finally, we illustrate that 
      Phi analysis, which has been widely used in protein folding studies, can 
      potentially generate new mechanistic information for long-range proton transfers 
      regarding the sequence of events. The results of the perturbation analysis and 
      the Phi analysis provide opportunities for experimentally testing the mechanistic 
      proposals from this study and our recent work in which a stepwise "proton hole" 
      transfer pathway has been proposed.
FAU - Riccardi, Demian
AU  - Riccardi D
AD  - Department of Chemistry and Program of Computation and Informatics in Biology and 
      Medicine, University of Wisconsin, 1101 University Avenue, Madison, Wisconsin 
      53706, USA.
FAU - Konig, Peter
AU  - Konig P
FAU - Guo, Hua
AU  - Guo H
FAU - Cui, Qiang
AU  - Cui Q
LA  - eng
GR  - R03AI068672/AI/NIAID 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.
DEP - 20080202
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (Mutant Proteins)
RN  - 0 (Protons)
RN  - 4QD397987E (Histidine)
RN  - EC 4.2.1.- (Carbonic Anhydrase II)
SB  - IM
MH  - Amino Acid Motifs
MH  - Binding Sites
MH  - Carbonic Anhydrase II/*chemistry/genetics/metabolism
MH  - Computer Simulation
MH  - Histidine/chemistry/physiology
MH  - Ion Exchange
MH  - Models, Molecular
MH  - Molecular Conformation
MH  - Mutagenesis, Site-Directed
MH  - Mutant Proteins/chemistry/metabolism
MH  - Protein Binding
MH  - Protein Folding
MH  - *Protons
MH  - Static Electricity
EDAT- 2008/02/06 09:00
MHDA- 2008/05/07 09:00
CRDT- 2008/02/06 09:00
PHST- 2008/02/06 09:00 [pubmed]
PHST- 2008/05/07 09:00 [medline]
PHST- 2008/02/06 09:00 [entrez]
AID - 10.1021/bi701950j [doi]
PST - ppublish
SO  - Biochemistry. 2008 Feb 26;47(8):2369-78. doi: 10.1021/bi701950j. Epub 2008 Feb 2.