Accelerated molecular dynamics (aMD) simulation is employed to study the functional dynamics of the flexible loop 3-4 in the strong-binding streptavidin-biotin complex system. Conventional molecular (cMD) simulation is also performed for comparison. The present study reveals the following important properties of the loop dynamics: (1) The transition of loop 3-4 from open to closed state is observed in 200 ns aMD simulation. (2) In the absence of biotin binding, the open-state streptavidin is more stable, which is consistent with experimental evidences. The free energy (Î "G) difference is about 5 kcal/mol between two states. But with biotin binding, the closed state is more stable due to electrostatic and hydrophobic interactions between the loop 3-4 and biotin. (3) The closure of loop 3-4 is concerted to the stable binding of biotin to streptavidin. When the loop 3-4 is in its open-state, biotin moves out of the binding pocket, indicating that the interactions between the loop 3-4 and biotin are essential in trapping biotin in the binding pocket. (4) In the tetrameric streptavidin system, the conformational change of the loop 3-4 in each monomer is independent of each other. That is, there is no cooperative binding for biotin bound to the four subunits of the tetramer.
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