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Human carbonic anhydrase II (HCA II) is an enzyme that catalyzes the reversible hydration of CO 2 into bicarbonate (HCO 3  - ) and a proton (H + ) as well as other reactions at an extremely high rate. This enzyme plays fundamental roles in human physiology/pathology, such as controlling the pH level in cells and so on. However, the binding mechanism between apo-HCA II and CO 2 or other ligands as well as related conformational changes remains poorly understood, and atomic investigation into it could promote our understanding of related internal physiological/pathological mechanisms. In this study, long-time atomic molecular dynamics simulations as well as the clustering and free-energy analysis were performed to reveal the dynamics of apo-HCA II as well as the mechanism upon ligand binding. Our simulations indicate that the crystallographic B-factors considerably underestimate the loop dynamics: multiple conformations can be adopted by loops 1 and 2, especially for loop 1 because loop 1 is one side of the binding pocket, and its left-to-right movement can compress or extend the binding pocket, leading to one inactive (closed) state, three intermediate (semiopen) states, and one active (open) state; CO 2 cannot get into the binding pocket of the inactive state but can get into those of intermediate and active states. The coexistence of multiple conformational states proposes a possible conformational selection model for the binding mechanism between apo-HCA II and CO 2 or other ligands, revising our previous view of its functional mechanism of conformational change upon ligand binding and offering valuable structural insights into the workings of HCA II.

Network of Conformational Transitions Revealed by Molecular Dynamics Simulations of the Carbonic Anhydrase II Apo-Enzyme