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@proceedings{949944,
author = {Wiesner, Jiří and Koča, Jaroslav},
booktitle = {Modeling Interactions in Biomolecules V},
keywords = {acetylcholinesterase; pKa; thermodynamic integration; umbrella sampling; charged species transport; electrostatic potetial; glutamic acid},
language = {eng},
isbn = {978-80-7378-180-4},
title = {pKa Calculation for Selected Active Site Residues in Acetylcholinesterase},
year = {2011}
}
TY - CONF
ID - 949944
AU - Wiesner, Jiří - Koča, Jaroslav
PY - 2011
TI - pKa Calculation for Selected Active Site Residues in Acetylcholinesterase
SN - 9788073781804
KW - acetylcholinesterase
KW - pKa
KW - thermodynamic integration
KW - umbrella sampling
KW - charged species transport
KW - electrostatic potetial
KW - glutamic acid
N2 - Acetylcholinesterase (AChE) is a vitally important enzyme participating in nerve signal transmission connected with Alzheimer disease and nerve agent poisoning. Molecular dynamics simulations in the Amber force field 03 have revealed large conformational changes of the omega loop (Cys69 – Cys96 in 2HA2 crystal structure) occurring when AChE is in its deprotonated state [1]. According to the ff03 MD results, the omega loop dynamics is dependent of the protonation of active site residues, namely Glu202, Glu334, Glu450 (numbering of 2HA2). Simulations of the protonated AChE show much more stable and less mobile omega loop and Trp86. Such omega loop conformations are not seen in any of the crystal structures of AChE. Furthermore, a great deal of experimental evidence disproves that larger conformational rearrangements of omega loop would take part in the reaction mechanism [2]. pKa calculations [3] for the selected active site residues – Glu202, Glu334, Glu450 – were performed by the means of thermodynamic integration using a non-polarisable force field potential – Amber ff09SB, and pKa shifts were obtained. The pKa calculation revealed clearly that there is a preferred protonation state for AChE. Two out of the three Glu residues located in the active site should be protonated. Glu450 appears to be the most acidic residue in the fully protonated state, but the values for Glu334 and Glu202, being close to the physiological pH value, do not exclude the possibility of a viable deprotonation pathway either. It is not possible to determine the preferred protonation state more exactly, since the pKa values are overestimated.
ER -
WIESNER, Jiří a Jaroslav KOČA. pKa Calculation for Selected Active Site Residues in Acetylcholinesterase. In \textit{Modeling Interactions in Biomolecules V}. 2011. ISBN~978-80-7378-180-4.
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