PMID- 21232525
OWN - NLM
STAT- MEDLINE
DCOM- 20110428
LR  - 20211020
IS  - 0006-3002 (Print)
IS  - 0006-3002 (Linking)
VI  - 1807
IP  - 4
DP  - 2011 Apr
TI  - Exploration of the cytochrome c oxidase pathway puzzle and examination of the 
      origin of elusive mutational effects.
PG  - 413-26
LID - 10.1016/j.bbabio.2011.01.004 [doi]
AB  - Gaining detailed understanding of the energetics of the proton-pumping process in 
      cytochrome c oxidase (CcO) is a problem of great current interest. Despite 
      promising mechanistic proposals, so far, a physically consistent model that would 
      reproduce all the relevant barriers needed to create a working pump has not been 
      presented. In addition, there are major problems in elucidating the origin of key 
      mutational effects and in understanding the nature of the apparent pK(a) values 
      associated with the pH dependencies of specific proton transfer (PT) reactions in 
      CcO. This work takes a key step in resolving the above problems, by considering 
      mutations, such as the Asn139Asp replacement, that blocks proton pumping without 
      affecting PT to the catalytic site. We first introduce a formulation that makes 
      it possible to relate the apparent pK(a) of Glu286 to different conformational 
      states of this residue. We then use the new formulation along with the calculated 
      pK(a) values of Glu286 at these different conformations to reproduce the 
      experimentally observed apparent pK(a) of the residue. Next, we take the X-ray 
      structures of the native and Asn139Asp mutant of the Paracoccus denitrificans CcO 
      (N131D in this system) and reproduce for the first time the change in the primary 
      PT pathways (and other key features) based on simulations that start with the 
      observed structural changes. We also consider the competition between proton 
      transport to the catalytic site and the pump site, as a function of the bulk pH, 
      as well as the H/D isotope effect, and use this information to explore the 
      relative height of the two barriers. The paper emphasizes the crucial role of 
      energy-based considerations that include the PT process, and the delicate control 
      of PT in CcO.
CI  - Copyright (c) 2011 Elsevier B.V. All rights reserved.
FAU - Chakrabarty, Suman
AU  - Chakrabarty S
AD  - Department of Chemistry, University of Southern California, 418 SGM Building, 
      3620 McClintock Avenue, Los Angeles, CA 90089-1062, USA.
FAU - Namslauer, Ida
AU  - Namslauer I
FAU - Brzezinski, Peter
AU  - Brzezinski P
FAU - Warshel, Arieh
AU  - Warshel A
LA  - eng
GR  - R01 GM040283/GM/NIGMS NIH HHS/United States
GR  - R01 GM040283-23/GM/NIGMS NIH HHS/United States
GR  - R01 GM040283-24/GM/NIGMS NIH HHS/United States
GR  - GM40283/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110110
PL  - Netherlands
TA  - Biochim Biophys Acta
JT  - Biochimica et biophysica acta
JID - 0217513
RN  - EC 1.9.3.1 (Electron Transport Complex IV)
SB  - IM
MH  - Electron Transport Complex IV/*chemistry/genetics/*metabolism
MH  - Kinetics
MH  - Models, Molecular
MH  - *Mutation
MH  - Paracoccus denitrificans/*enzymology
MH  - Protein Structure, Tertiary
PMC - PMC3055932
MID - NIHMS264852
EDAT- 2011/01/15 06:00
MHDA- 2011/04/29 06:00
PMCR- 2012/04/01
CRDT- 2011/01/15 06:00
PHST- 2010/09/30 00:00 [received]
PHST- 2010/12/22 00:00 [revised]
PHST- 2011/01/05 00:00 [accepted]
PHST- 2011/01/15 06:00 [entrez]
PHST- 2011/01/15 06:00 [pubmed]
PHST- 2011/04/29 06:00 [medline]
PHST- 2012/04/01 00:00 [pmc-release]
AID - S0005-2728(11)00006-5 [pii]
AID - 10.1016/j.bbabio.2011.01.004 [doi]
PST - ppublish
SO  - Biochim Biophys Acta. 2011 Apr;1807(4):413-26. doi: 10.1016/j.bbabio.2011.01.004. 
      Epub 2011 Jan 10.