Molecular dynamics study on the behavior and binding mechanism of target protein Transgelin-2 with its agonist TSG12 for anti-asthma drug discovery.

Transgelin-2 (TG2) is a novel promising therapeutic target for the treatment of asthma as it plays an important role in relaxing airway smooth muscles and reducing pulmonary resistance in asthma. The compound TSG12 is the only reported TG2 agonist with in vivo anti-asthma activity. However, the dynamic behavior and ligand binding sites of TG2 and its binding mechanism with TSG12 remain unclear. In this study, we performed 12.6 μs molecular dynamics (MD) simulations for apo-TG2 and TG2-TSG12 complex, respectively. The results suggested that the apo-TG2 has 4 most populated conformations, and that its binding of the agonist could expand the conformation distribution space of the protein. The simulations revealed 3 potential binding sites in 3 most populated conformations, one of which is induced by the agonist binding. Free energy decomposition uncovered 8 important residues with contributions stronger than -1 kcal/mol. Computational alanine scanning for the important residues by 100 ns conventional MD simulation for each mutated TG2-TSG12 complexes demonstrated that E27, R49 and F52 are essential residues for the agonist binding. These results should be helpful to understand the dynamic behavior of TG2 and its binding mechanism with the agonist TSG12, which could provide some structural insights into the novel mechanism for anti-asthma drug development.