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The mechanism of l-lactate generation from pyruvate by l-lactate dehydrogenase (LDH) from the rabbit muscle was studied theoretically by the multistructural microiteration (MSM) method combined with the quantum mechanics/molecular mechanics (QM/MM)-ONIOM method, where the MSM method describes the MM environment as a weighted average of multiple different structures that are fully relaxed during geometry optimization or a reaction path calculation for the QM part. The results showed that the substrate binding and product states were stabilized only in the open-loop conformation of LDH and the reaction occurred in the closed-loop conformation. In other words, before and after the chemical reaction, a large-scale structural transition from the open-loop conformation to the closed-loop conformation and vice versa occurred. The closed-loop conformation stabilized the transition state of the reaction. In contrast, the open-loop conformation stabilized the substrate binding and final states. In other words, the closed- to open-loop transition at the substrate binding state urges capture of the substrate molecule, the subsequent open- to closed-loop transition promotes the product generation, and the final closed- to open-loop transition at the final state prevents the reverse reaction going back to the substrate binding state. It is thus suggested that the exchange of stability between the closed- and open-loop conformations at different states promotes the catalytic cycle.

Roles of Closed- and Open-Loop Conformations in Large-Scale Structural Transitions of l-Lactate Dehydrogenase