Long Time-Scale Atomistic Simulations of the Structure and Dynamics of Transcription Factor-DNA Recognition

Abstract

p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 12.0px 'Helvetica Neue'} <p>Recent years have witnessed an explosion of interest in computational studies of DNA binding proteins, including both coarse grained and atomistic simulations of transcription factor-DNA recognition, in order to understand how these transcription factors recognize their binding sites on the DNA with such exquisite specificity. The present study performs μs-timescale all-atom simulations of the dimeric form of the lactose repressor (LacI), both in the absence of any DNA, and in the presence of both specific and non-specific complexes, considering three different DNA sequences. We examine, specifically, the conformational differences between specific and non-specific protein-DNA interactions, as well as the behavior of the helix-turn-helix motif of LacI when interacting with the DNA. Our simulations suggest that stable LacI binding occurs primarily to bent A-form DNA, with a loss of LacI conformational entropy and optimization of correlated conformational equilibria across the protein. In addition, binding to the specific operator sequence involves a slightly larger number of stabilizing DNA-protein hydrogen bonds (in comparison to non-specific complexes), that may account for the experimentally observed specificity for this operator. In doing so, our simulations provide a detailed atomistic description of potential structural drivers for LacI selectivity.</p>

The N-Terminal Helix-Turn-Helix Motif of Transcription Factors MarA and Rob Drives DNA Recognition

“…Curiously, however, MarA interacts with the DNA with at both the A-box and the B-box, whereas Rob only interacts with the DNA at the A-box (Figure 1), without significantly compromising the binding affinity of DNA to Rob (Table S2) (23). We hypothesize that these two very different DNA binding modes result from differential dynamics at the binding interface, as such dynamics has been suggested to be important in other systems (11,34,68). These can result from differences in the intrinsic flexibility of the two proteins, sequence-specific differences in the intrinsic flexibility of the DNA, or differences in both protein and DNA simultaneously.…”

“…This is supported by a substantial history of MD simulation of protein-DNA binding (34), allostery (35), effect of ions (36), and contact dynamics (37). We recently performed multimicrosecond all-atom simulations of LacI-DNA interactions, exploring the interactions between LacI and both specific and non-specific DNA sequences (11). These simulations suggested, in agreement with experimental observations (38), that stable LacI binding occurs primarily to bent A-form DNA and helped explain the molecular interactions contributing to specific binding.…”

“…The molecular details of protein-DNA recognition and selectivity are thus of great biochemical interest and biological significance, as are the mechanisms by which DNA-binding proteins can rapidly identify their specific DNA binding sites from amongst a multitude of non-specific DNA sites (8). There has been substantial experimental (9,10) and computational (11)(12)(13) progress towards understanding how transcription factors search DNA for their target sites. This has been aided by recent improvements in computational power that enable the study of protein-DNA recognition on the microsecond timescale using all-atom models (11).…”

“…There has been substantial experimental (9,10) and computational (11)(12)(13) progress towards understanding how transcription factors search DNA for their target sites. This has been aided by recent improvements in computational power that enable the study of protein-DNA recognition on the microsecond timescale using all-atom models (11).…”

Inchworm stepping of Myc-Max heterodimer protein diffusion along DNA

“…On the other hand, structure-based simulations allow for molecular dynamics (MD) characterization of key structure components of the systems. Atomic MD simulations contain finest structural dynamics details but are often limited by simulation time scale, which can hardly surpass several microseconds for a TF protein-DNA system of a regular size [18][19][20]. Coarse-graining (CG) techniques, however, provide ways to extend the simulation time scale via maintaining essential protein-DNA electrostatic interactions to support the TF diffusion [21][22][23][24].…”