TY - JOUR
T1 - Coupling between protonation and conformation in cytochrome c oxidase
T2 - Insights from constant-pH MD simulations
AU - Oliveira, A. Sofia F
AU - Campos, Sara R R
AU - Baptista, António M.
AU - Soares, Cláudio M.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - Cytochrome c oxidases (CcOs) are the terminal enzymes of the respiratory chain in mitochondria and most bacteria. These enzymes reduce dioxygen (O2) to water and, simultaneously, generate a transmembrane electrochemical proton gradient. Despite their importance in the aerobic metabolism and the large amount of structural and biochemical data available for the A1-type CcO family, there is still no consensually accepted description of the molecular mechanisms operating in this protein. A substantial number of questions about the CcO's working mechanism remain to be answered, including how the protonation behavior of some key residues is modulated during a reduction cycle and how is the conformation of the protein affected by protonation. The main objective of this work was to study the protonation-conformation coupling in CcOs and identify the molecular factors that control the protonation state of some key residues. In order to directly capture the interplay between protonation and conformational effects, we have performed constant-pH MD simulations of an A1-type CcO inserted into a lipid bilayer in two redox states (oxidized and reduced) at physiological pH. From the simulations, we were able to identify several groups with unusual titration behavior that are highly dependent on the protein redox state, including the A-propionate from heme a and the D-propionate from heme a3, two key groups possibly involved in proton pumping. The protonation state of these two groups is heavily influenced by subtle conformational changes in the protein (notably of R481I and R482I) and by small changes in the hydrogen bond network.
AB - Cytochrome c oxidases (CcOs) are the terminal enzymes of the respiratory chain in mitochondria and most bacteria. These enzymes reduce dioxygen (O2) to water and, simultaneously, generate a transmembrane electrochemical proton gradient. Despite their importance in the aerobic metabolism and the large amount of structural and biochemical data available for the A1-type CcO family, there is still no consensually accepted description of the molecular mechanisms operating in this protein. A substantial number of questions about the CcO's working mechanism remain to be answered, including how the protonation behavior of some key residues is modulated during a reduction cycle and how is the conformation of the protein affected by protonation. The main objective of this work was to study the protonation-conformation coupling in CcOs and identify the molecular factors that control the protonation state of some key residues. In order to directly capture the interplay between protonation and conformational effects, we have performed constant-pH MD simulations of an A1-type CcO inserted into a lipid bilayer in two redox states (oxidized and reduced) at physiological pH. From the simulations, we were able to identify several groups with unusual titration behavior that are highly dependent on the protein redox state, including the A-propionate from heme a and the D-propionate from heme a3, two key groups possibly involved in proton pumping. The protonation state of these two groups is heavily influenced by subtle conformational changes in the protein (notably of R481I and R482I) and by small changes in the hydrogen bond network.
KW - Computer simulation
KW - Constant pH molecular dynamics (constant-pH MD) simulations
KW - Cytochrome c oxidase
KW - Proton transfer
KW - Protonation-conformation coupling
KW - Redox-dependent change
UR - http://www.scopus.com/inward/record.url?scp=84964689558&partnerID=8YFLogxK
U2 - 10.1016/j.bbabio.2016.03.024
DO - 10.1016/j.bbabio.2016.03.024
M3 - Article
C2 - 27033303
AN - SCOPUS:84964689558
SN - 0005-2728
VL - 1857
SP - 759
EP - 771
JO - Biochimica et Biophysica Acta-Bioenergetics
JF - Biochimica et Biophysica Acta-Bioenergetics
IS - 6
ER -