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

Area of Science:

• Biochemistry
• Computational Chemistry
• Enzymology

Background:

• L-lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to l-lactate, a crucial step in cellular metabolism.
• Understanding the precise conformational dynamics of LDH during catalysis is essential for elucidating its reaction mechanism.

Purpose of the Study:

• To theoretically investigate the catalytic mechanism of l-lactate generation by rabbit muscle LDH.
• To elucidate the role of conformational changes in substrate binding, transition state stabilization, and product release.

Main Methods:

• Multistructural microiteration (MSM) method combined with QM/MM-ONIOM approach.
• Simulating the molecular mechanics (MM) environment as a weighted average of multiple relaxed structures.
• Performing quantum mechanics (QM) calculations for reaction path and geometry optimization.

Main Results:

• Substrate binding and product states are stabilized in the open-loop conformation of LDH.
• The chemical reaction occurs in the closed-loop conformation, which stabilizes the transition state.
• Large-scale conformational transitions between open-loop and closed-loop states facilitate the catalytic cycle.

Conclusions:

• The catalytic cycle of LDH is promoted by the exchange of stability between closed- and open-loop conformations at different functional states.
• Conformational transitions are critical for substrate capture, product formation, and preventing reverse reactions.
• This study provides a detailed theoretical insight into the dynamic mechanism of LDH-catalyzed l-lactate production.