Exploring LacI–DNA Dynamics by Multiscale Simulations Using the SIRAH Force Field

The lac repressor protein (LacI) together with its target regulatory sequence are a common model for studying DNA looping and its implications on transcriptional control in bacteria. Owing to the molecular size of this system, standard all-atom (AA) simulations are prohibitive for achieving relevant biological time scales. As an alternative, multiscale models, which combine AA descriptions at particular regions with coarse-grained (CG) representations of the remaining components, were used to address this computational challenge while preserving the relevant details of the system. In this work, we implement a new multiscale approach based on the SIRAH force field to gain deeper insights into the dynamics of the LacI-DNA system. Our methodology allows for a dual resolution treatment of the solute and solvent, explicitly representing the protein, DNA, and solvent environment without compromising the AA region. Starting from the P1 loop configuration in an undertwisted conformation, we were able to observe the transition to the more stable overtwisted state. Additionally, a detailed characterization of the conformational space sampled by the DNA loop was done. In agreement with experimental and theoretical evidence, we observed the transient formation of kinks at the loop, which were stabilized by the presence of counterions at the minor groove. We also show that the loop's intrinsic flexibility can account for reported FRET measurements and bent conformations required to bind the CAP transcription factor.