TY - GEN
T1 - Multiple oxygen entry pathways in globin proteins revealed by intrinsic pathway identification method
AU - Takayanagi, Masayoshi
AU - Kurisaki, Ikuo
AU - Nagaoka, Masataka
N1 - Funding Information:
This work was partially supported by financial supports from JSPS KAKENHI from The Ministry of Education, Culture, Sports, Science and Technology (MEXT) and CREST "High Performance Computing for Multi-scale and Multi-physics Phenomena", "Creation of Innovative Functional Materials with Advanced Properties by Hyper-nano-space Design" and "Establishment of Molecular Technology towards the Creation of New Functions" from the Japan Science and Technology Agency (JST). Author 2 also thanks for the support from JSPS by the Research Fellowship for Young Scientist.
Publisher Copyright:
© 2015 AIP Publishing LLC.
PY - 2015/12/31
Y1 - 2015/12/31
N2 - Each subunit of human hemoglobin (HbA) stores an oxygen molecule (O2) in the binding site (BS) cavity near the heme group. The BS is buried in the interior of the subunit so that there is a debate over the O2 entry pathways from solvent to the BS; histidine gate or multiple pathways. To elucidate the O2 entry pathways, we executed ensemble molecular dynamics (MD) simulations of T-state tetramer HbA in high concentration O2 solvent to simulate spontaneous O2 entry from solvent into the BS. By analyzing 128 independent 8 ns MD trajectories by intrinsic pathway identification by clustering (IPIC) method, we found 141 and 425 O2 entry events into the BS of the α and β subunits, respectively. In both subunits, we found that multiple O2 entry pathways through inside cavities play a significant role for O2 entry process of HbA. The rate constants of O2 entry estimated from the MD trajectories correspond to the experimentally observed values. In addition, by analyzing monomer myoglobin, we verified that the high O2 concentration condition can reproduce the ratios of each multiple pathway in the one-tenth lower O2 concentration condition. These indicate the validity of the multiple pathways obtained in our MD simulations.
AB - Each subunit of human hemoglobin (HbA) stores an oxygen molecule (O2) in the binding site (BS) cavity near the heme group. The BS is buried in the interior of the subunit so that there is a debate over the O2 entry pathways from solvent to the BS; histidine gate or multiple pathways. To elucidate the O2 entry pathways, we executed ensemble molecular dynamics (MD) simulations of T-state tetramer HbA in high concentration O2 solvent to simulate spontaneous O2 entry from solvent into the BS. By analyzing 128 independent 8 ns MD trajectories by intrinsic pathway identification by clustering (IPIC) method, we found 141 and 425 O2 entry events into the BS of the α and β subunits, respectively. In both subunits, we found that multiple O2 entry pathways through inside cavities play a significant role for O2 entry process of HbA. The rate constants of O2 entry estimated from the MD trajectories correspond to the experimentally observed values. In addition, by analyzing monomer myoglobin, we verified that the high O2 concentration condition can reproduce the ratios of each multiple pathway in the one-tenth lower O2 concentration condition. These indicate the validity of the multiple pathways obtained in our MD simulations.
KW - Clustering
KW - Hemoglobin
KW - Ligand Dynamics
KW - Molecular Dynamics
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U2 - 10.1063/1.4938872
DO - 10.1063/1.4938872
M3 - Conference contribution
AN - SCOPUS:84984567315
T3 - AIP Conference Proceedings
BT - International Conference of Computational Methods in Sciences and Engineering 2015, ICCMSE 2015
A2 - Kalogiratou, Zacharoula
A2 - Simos, Theodore E.
A2 - Monovasilis, Theodore
A2 - Simos, Theodore E.
A2 - Simos, Theodore E.
PB - American Institute of Physics Inc.
T2 - International Conference of Computational Methods in Sciences and Engineering 2015, ICCMSE 2015
Y2 - 20 March 2015 through 23 March 2015
ER -