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

Abstract

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.

Adaptive resolution simulation of an atomistic DNA molecule in MARTINI salt solution

“…We would like to emphasize that the coupling of the salt solutions allows similar applications (hydration shell as well as drug binding) in case of other biomolecules. Further broadening the application range is the possibility of dual-resolution representation of not only the solvent but also of the biomolecules themselves, as is done, for example, in the model of Pantani and co-workers [66,67].…”

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“…AMBER is generally used for simulating DNA structure to find out the most suitable conformation 12 . Moreover, newly discovered force field named as 'parmbsc1' and SIRAH are very useful for atomistic simulation of almost DNA structure space 13,14 . The polarizable force fields came up based on the different charges and theories.…”

“…Expanding the position of the i th particle having r i position at time t + ∆t and t -∆t and b i as the third derivative of r i (12) (13) O(∆t 4 ) is local error in position of Verlet integrator. Adding the expression (12) and (13) (14) Equate equation (14) by putting a i = F i / m i (15) The equation (12) and (13) constitute the basic form of the Verlet algorithm.…”

“…6 a, 6b, 6c and 6d highlighting different methods based DNA/RNA simulation: (a) the joint QM/MM work from the Magistrato's group, explaining the atomistic and energetic variations of human Flap endonucleases (FENs) with DNA and RNA complex using mixed quantum-classical (QM/MM) metadynamics and umbrella sampling free energy calculations 49 . (b) Explains how DNA Hollidayjunction simulated with the new force parmBSC1 13 . (c) An implementation of new force SIRAH force field into LacI-DNA system using twofold resolution treatment of the solute and solvent without compromising the AA region 14 .…”

“…They have highlighted four applications of MD simulation (a) the combined QM/MM work from the Magistrato's group, were a protein-DNA complex with a DNA lesion is studied in detail 18 . (b) Holliday-junction simulated with the new parmBSC1 refined force-field for DNA simulations, adapted from 13 . (c) LacI-DNA dynamics by multiscale simulations using the SIRAH force-field from Pantano's group 14 .…”