Exploring LacI-DNA dynamics by multiscale simulations using the SIRAH force field.

Area of Science:

• Biophysics
• Computational Biology
• Molecular Biology

Background:

• The lac repressor protein (LacI)-DNA system is a key model for studying bacterial transcriptional control and DNA looping.
• All-atom simulations of this large system are computationally expensive, limiting exploration of biological time scales.

Purpose of the Study:

• To implement and utilize a novel multiscale simulation method for investigating the LacI-DNA system dynamics.
• To overcome computational limitations of all-atom simulations for large biomolecular systems.

Main Methods:

• Employed a multiscale modeling approach combining all-atom (AA) and coarse-grained (CG) representations.
• Utilized the SIRAH force field for a dual-resolution treatment of solute and solvent.
• Simulated the LacI-DNA system starting from an undertwisted P1 loop conformation.

Main Results:

• Observed the transition of the LacI-DNA loop from an undertwisted to a more stable overtwisted state.
• Characterized the DNA loop's conformational space, noting transient kink formation stabilized by counterions.
• Demonstrated that loop flexibility explains FRET measurements and CAP transcription factor binding conformations.

Conclusions:

• The multiscale approach provides a computationally efficient method for studying complex biomolecular systems like LacI-DNA.
• The findings elucidate the dynamic conformational behavior of DNA loops and their role in gene regulation.
• This methodology offers deeper insights into the molecular mechanisms underlying transcriptional control in bacteria.