Elizabeth Villa, Alexander Balaeff, and Klaus Schulten.
Structural dynamics of the Lac repressor-DNA complex
revealed by a multiscale simulation.
Proceedings of the National Academy of Sciences, USA,
102:6783-6788, 2005.
(PMC: 1100768)
VILL2005
A multiscale simulation of a complex between the lac repressor
protein (LacI) and a 107 base pair (bp)-long DNA segment is
reported. The complex between the repressor and two operator DNA
segments is described by all-atom molecular dynamics (MD); 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 non-linear Kirchhoff
differential equations with boundary conditions obtained from the
coordinates of the terminal base pairs of each operators. The forces
stemming from the looped DNA are included in the MD simulations; the
loop structure and the forces are continuously recomputed as the
protein motions during the simulations shift the operators and the
presumed termini of the loop. The simulations reveal the structural
dynamics of the LacI-DNA complex in unprecedented detail. The multiple
domains of LacI exhibit remarkable structural stability during the
simulation, moving much like rigid bodies. LacI 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 LacI by 500 pN forces revealed the interactions responsible for locking LacI in the V-conformation.
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