Ligands-induced open-close conformational change during DapE catalysis: Insights from molecular dynamics simulations

The microbial enzyme DapE plays a critical role in the lysine biosynthetic pathway and is considered as a potentially safe antibiotic target. In this study, atomistic simulations are employed to identify the modes of essential dynamics that define the conformational response of the enzyme to ligand binding and unbinding. The binding modes and the binding affinities of the products to the DapE enzyme are estimated from the MM-PBSA method, and the residues contributing to the ligand binding are identified. Various structural analyses and the principal component analysis of the molecular dynamics trajectories reveal that the removal of products from the active site causes a significant change in the overall enzyme structure. Both Cartesian and dihedral principal component analyses are used to characterize the structural changes in terms of domain unfolding and domain twisting motions. In the most dominant mode, that is, the domain unfolding motion, the two catalytic domains move away from the two dimerization domains of the dimeric enzyme, representing a closed-to-open conformational change. The conformational changes are initiated by the coordinated movement of three loops (Asp75-Pro82, Gly240-Asn244, and Thr347-Glu353) that trigger a domain-level movement. From multiple short trajectories, the time constant associated with the domain opening motion is estimated as 43.6 ns. Physiologically, this close-to-open conformational change is essential for the regeneration of the initial state of the enzyme for the subsequent cycle of catalytic action and provides the apo enzyme enough flexibility for efficient substrate binding.