The Loop Opening/Closing Motion of the Enzyme Triosephosphate Isomerase
To explore the origin of the large-scale motion of triosephosphate isomerase's
flexible loop (residues 166 to 176) at the active site, several simulation
protocols are employed both for the free enzyme in vacuo and for the free
enzyme with some solvent modeling: high-temperature Langevin dynamics simulations,
sampling by a "dynamics driver" approach, and potential-energy surface
calculations. Our focus is on obtaining the energy barrier to the enzyme's
motion and establishing the nature of the loop movement. Previous calculations
did not determine this energy barrier and the effect of solvent on the
barrier. High-temperature molecular dynamics simulations and crystallographic
studies have suggested a rigid-body motion with two hinges located at both
ends of the loop; Brownian dynamics simulations at room temperature pointed
to a very flexible behavior. The present simulations and analyses reveal
that although solute/solvent hydrogen bonds play a crucial role in lowering
the energy along the pathway, there still remains a high activation barrier.
This finding clearly indicates that, if the loop opens and closes in the
absence of a substrate at standard conditions (e.g., room temperature,
appropriate concentration of isomerase), the time scale for transition
is not in the nanosecond but rather the microsecond range. Our results
also indicate that in the context of spontaneous opening in the free enzyme,
the motion is of rigid body type and that the specific interaction between
residues Ala176 and Tyr208 plays a crucial role in
the loop opening/closing mechanism.
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