Influence of the Acetylcholinesterase Active Site Protonation on Omega Loop and Active Site Dynamics

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Publikace nespadá pod Filozofickou fakultu, ale pod Přírodovědeckou fakultu. Oficiální stránka publikace je na webu muni.cz.
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WIESNER Jiří KŘÍŽ Zdeněk KUČA Kamil JUN Daniel KOČA Jaroslav

Rok publikování 2010
Druh Článek v odborném periodiku
Časopis / Zdroj Journal of Biomolecular Structure & Dynamics
Fakulta / Pracoviště MU

Přírodovědecká fakulta

Citace
Obor Fyzikální chemie a teoretická chemie
Klíčová slova acetylcholinesterase; molecular dynamics; protonation states; glutamic acid; omega loop
Popis Existence of alternative entrances in acetylcholinesterase (AChE) could explain the contrast between the very high AChE catalytic efficiency and the narrow and long access path to the active site revealed by X-ray crystallography. Alternative entrances could facilitate diffusion of the reaction products or at least water and ions from the active site. Previous molecular dynamics simulations identified side door and back door as the most probable alternative entrances. The simulations of non-inhibited AChE suggested that the back door opening events occur only rarely (0.8% of the time in the 10ns trajectory). Here we present a molecular dynamics simulation of non-inhibited AChE, where the back door opening appears much more often (14% of the time in the 12ns trajectory) and where the side door opening was observed quite frequently (78% of trajectory time). We also present molecular dynamics, where the back door does not open at all, or where large conformational changes of the AChE omega loop occur together with alternative passage opening events. All these differences in AChE dynamical behavior are caused by different protonation states of two glutamate residues located on bottom of the active site gorge (Glu202 and G450 in Mus musculus AChE). Our results confirm the results of previous molecular dynamics simulations, expand the view and suggest the probable reasons for the overall conformational behavior of AChE omega loop.
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