The catalytic His447 is more stable with Glu202 being
protonated
In our previous study, we found that the catalytic His438 of BChE is
eventually distorted after the collapse of the key hydrogen bond
network. It is thus interesting to know whether the same effects can be
observed in AChE. Shown in Figure 3A is the RMSD traces of the catalytic
His447 of AChE with Glu202 being protonated. Clearly, the His447 stays
firmly at its crystal structure position throughout the entire
simulation. However, from Figure 3A where Glu202 is deprotonated, the
RMSD traces indicate that the catalytic His447 stays at its crystal
structure position for only the initial 20 ns. Then, the His447 deviates
significantly from its crystal structure position. Shown in Figure 3C is
the His447 in the representative MD-simulated structure compared to that
in the crystal structure. Similar to what is observed for the key
hydrogen bond network, the simulated His447 is also almost identical to
that in the crystal structure. The distances of the two hydrogen bonds
in the catalytic triad are 2.4±0.8 Å and 1.8±0.1 Å, respectively,
indicating a stable catalytic triad throughout the simulation. However,
this catalytic triad is observed as disrupted in a simulation with
Glu202 being deprotonated. As we mentioned above, due to the repulsion
between the deprotonated Glu202 and the key water molecule, the key
hydrogen bond network is eventually collapsed. From Figure 4D, we can
see that the collapsed key hydrogen bond network produces an empty space
for the catalytic His447. This empty space decreases the stability of
His447 and promotes it to deviate largely from its crystal structure
position, causing the disruption of the catalytic triad.
Therefore, the key hydrogen bond network plays an important role in
stabilizing the catalytic triad through supporting the His447. Without
the key hydrogen bond network, the His447 could deviate largely to
occupy the space that originally belongs to the hydrogen bond network,
and this large deviation of His447 apparently results in the distortion
of the catalytic triad.