Recognition complex between the HMG domain of LEF-1 and its cognate DNA studied by molecular dynamics simulations with explicit solvation.

Molecular dynamics simulations of the complex formed between the HMG box of the lymphoid enhancer-binding factor (LEF-1) and its cognate DNA duplex were carried out with explicit inclusion of water. The simulation started with an NMR-based model (pdb code 2LEF) and the dynamics was pursued for 10 nanoseconds without constraints. It revealed that water intervenes in many ionic/polar interactions, establishing in particular local equilibria between direct and water-mediated hydrogen bonds, and thus increasing the entropy of the complex. Quite unexpectedly, the simulation indicated that a binding pocket for a specific water molecule may be reversibly formed at the apex of the bend induced in the DNA helix by LEF-1 binding, where a methionine side chain intercalates between two destacked adenines. We observed that the specific water molecule can temporarily replace the intercalated S-CH(3) group, acting as a sort of "extension" of the side chain. The residence time of this water molecule was about 3.5 ns. Simulations of the cognate DNA alone showed that this sequence has no intrinsic tendency to bend; therefore, the bending occurs solely as a consequence of the recognition, following the "induced-fit" mechanism.