Biomedical subjects

Alexander Balaeff

Publications and source records attributed to Alexander Balaeff.

3 recordsLinked to original sources

PubMed2006

Modeling DNA loops using the theory of elasticity.

An elastic rod model of a protein-bound DNA loop is adapted for application in multi-scale simulations of protein-DNA complexes. The classical Kirchhoff system of equations which describes the equilibrium structure of the elastic loop is modified to account for the intrinsic twist and curvature, anisotropic bending properties, and electrostatic charge of DNA. The effects of bending anisotropy and electrostatics are studied for the DNA loop clamped by the lac repressor protein. For two possible lengths of the loop, several topologically different conformations are predicted and extensively analyzed over the broad range of model parameters describing DNA bending and electrostatic properties. The scope and applications of the model in already accomplished and in future multi-scale studies of protein-DNA complexes are discussed.

Computer Simulation↗

PubMed2005

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

A multiscale simulation of a complex between the lac repressor protein (LacI) 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 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.

Computer Simulation↗

PubMed2004

Structural basis for cooperative DNA binding by CAP and lac repressor.

Catabolite gene activator protein (CAP) and lac repressor (LR) are celebrated transcription-regulating proteins that bind to DNA cooperatively forming a ternary complex with the promoter loop. Here we present a multiscale model of the ternary complex derived from crystal structures of the proteins and a continuous structure of the DNA loop built using the theory of elasticity. We predict that the loop is underwound in the binary complex with the LR, whereas in the ternary complex with the LR and CAP, the loop is overwound and extended due to an upstream relocation of a DNA binding hand of LR. The computed relocation distance matches the experimental observations and the energy balance of the system explains the cooperativity effect. Using the multiscale approach, we build an all-atom model of the ternary complex that suggests a series of further experimental investigations.

Binding, Competitive↗