Integrin alpha-2 I domain, the ligand binding domain of the signaling protein - integrin alpha-2, has two known conformations. They are specified as open and closed conformation that correspond to high and low binding affinity to ligands, respectively. The closed conformation is more stable in the ligand free state, and the open conformation is more populated when bound with ligand. The conformation change from closed to open is known to be triggered by a directional force on the C-terminal. To explain the mechanisms of the conformation change, we built a model of the I domain bound state in the closed conformation (C-terminal in closed conformation, MIDAS binding site in partially open conformation) using steered molecular dynamics simulation. Combining correlated motion analysis with gene sequence analysis, we found a clear pathway that transduces the pulling force between the C-terminal residues and ligand binding site. Residues in the pathway are well conserved among the evolution of integrin alpha-2. Further, in MM/PBSA energy calculation, the I domain is more stable in the unbound closed conformation than in unbound open conformation, which is consistent with experiments. However, the electrostatic force analysis indicates that the binding site in the closed conformation has stronger attractive electrostatic force to the ligand when they are separated by 5-20Å. In our model of the closed conformation in ligand bound state, the stability of the partially closed conformation falls in between of the closed and the open conformation. It indicates the existence of an I domain ligand bound closed conformation as an intermediate state between the open bound state and the closed unbound state.

Simulation study of integrin alpha-2 I domain activation

254th National Meeting (2017)

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