Structural dynamics of the lac repressor-DNA complex revealed by a multiscale simulation

摘要

A multiscale simulation of a complex between the lac repressor protein (Lacl) and a 107-bp-long DNA segment is reported. The complex between the repressor and two operator DNA segments is described by all-atom molecular dynamics; the size of the simulated system comprises either 226,000 or 314,000 atoms. The DNA loop connecting the operators is modeled as a continuous elastic ribbon, described mathematically by the nonlinear Kirchhoff differential equations with boundary conditions obtained from the coordinates of the terminal base pairs of each operator. The forces stemming from the looped DNA are included in the molecular dynamics simulations; the loop structure and the forces are continuously recomputed because the protein motions during the simulations shift the operators and the presumed termini of the loop. The simulations reveal the structural dynamics of the Lacl-DNA complex in unprecedented detail. The multiple domains of Lacl exhibit remarkable structural stability during the simulation, moving much like rigid bodies. Lacl is shown to absorb the strain from the looped DNA mainly through its mobile DNA-binding head groups. Even with large fluctuating forces applied, the head groups tilt strongly and keep their grip on the operator DNA, while the remainder of the protein retains its V-shaped structure. A simulated opening of the cleft of Lacl by 500-pN forces revealed the interactions responsible for locking Lacl in the V-conformation.