Coarse-grained modeling of DNA curvature

Freeman, Gordon S.; Hinckley, Daniel M.; Lequieu, Joshua; Whitmer, Jonathan K.; Pablo, Juan J. de

doi:10.1063/1.4897649

Cited by 125 publications

(230 citation statements)

References 38 publications

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“…Briefly, the simulations were carried out using electrostatically enhanced version of AWSEM force field for proteins (33) and 3SPN2c force field for DNA (22,23). All simulations were done under constant temperature conditions, following the standard protocols of minimization and equilibration starting from either computationally predicted or available crystal structures.…”

Section: Methodsmentioning

confidence: 99%

“…1B) we carried out simulations with a coarse-grained protein-DNA force field. We added the missing molecular fragments and regenerated the full structures of the various complexes by using the Associative memory, Water mediated, Structure and Energy Model (AWSEM) for the interactions within and among the proteins (21) and the Three Sites Per Nucleotide (3SPN) model for the DNA (22,23). DNA and protein are coupled through steric exclusion and electrostatics modeled at the mean field level.…”

Section: Structures Dynamics and Thermodynamicsmentioning

confidence: 99%

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Molecular stripping in the NF-κB/IκB/DNA genetic regulatory network

Potoyan

Zheng

Komives

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

119

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Genetic switches based on the NF-κB/ IκB/ DNA system are master regulators of an array of cellular responses. Recent kinetic experiments have shown that IκB can actively remove NF-κB bound to its genetic sites via a process called "molecular stripping." This allows the NF-κB/ IκB/ DNA switch to function under kinetic control rather than the thermodynamic control contemplated in the traditional models of gene switches. Using molecular dynamics simulations of coarse-grained predictive energy landscape models for the constituent proteins by themselves and interacting with the DNA we explore the functional motions of the transcription factor NF-κB and its various binary and ternary complexes with DNA and the inhibitor IκB. These studies show that the function of the NF-κB/ IκB/ DNA genetic switch is realized via an allosteric mechanism. Molecular stripping occurs through the activation of a domain twist mode by the binding of IκB that occurs through conformational selection. Free energy calculations for DNA binding show that the binding of IκB not only results in a significant decrease of the affinity of the transcription factor for the DNA but also kinetically speeds DNA release. Projections of the free energy onto various reaction coordinates reveal the structural details of the stripping pathways. T he binding and release of protein transcription factors from DNA are fundamental molecular processes by which genes are regulated in the cell. The pioneering studies of Jacob, Monod, Ptashne, and Gilbert explained how these two processes, seeming inverses of each other, while being maintained in local chemical equilibrium, could still lead to robust genetic switches by coupling to protein synthesis and degradation, which are kinetically controlled far from equilibrium processes (1-4). This classic picture, with the law of mass action at its core (5, 6), suggests that understanding the molecular mechanism of the binding and release of transcription factors is of secondary interest compared with understanding the thermodynamics of protein-DNA recognition. The recent discovery of proteininduced release of a DNA-bound transcription factor in the NF-κB=IκB=DNA genetic switch changes this picture (7). The induced process, called "molecular stripping," opens up the possibility of molecular kinetic control of binding and release, thus overturning the classic paradigm based only on thermodynamic control. In this paper, we use molecular dynamics simulations of coarse-grained but predictive energy landscape models of the proteins along with their interacting DNA to explore first how the NF-κB transcription factor binds individually both to DNA and to its inhibitor IκB and then to study how an approaching IκB can strip the NF-κB from a DNA molecule to which it has already been bound, by forming an intermediate ternary complex. These simulations show that each of the binary binding events involves conformational selection of different NF-κB global conformations. Molecular stripping then occurs that is induced by forming the ternar...

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Section: Methodsmentioning

confidence: 99%

Section: Structures Dynamics and Thermodynamicsmentioning

confidence: 99%

Molecular stripping in the NF-κB/IκB/DNA genetic regulatory network

Potoyan

Zheng

Komives

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

119

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show abstract

“…1B) we carried out simulations with a coarse-grained protein-DNA force field. We added the missing molecular fragments and re-generated the full structures of the various complexes by using the Associative memory, Water mediated, Structure and Energy Model (AWSEM) for the interactions within and among the proteins (21) and the 3 Sites Per Nucleotide (3SPN) model for the DNA (22,23). DNA and protein are coupled through steric exclusion and electrostatics modeled at the mean field level.…”

Section: Structures Dynamics and Thermodynamicsmentioning

confidence: 99%

Molecular stripping in the NFκB/IκB/DNA genetic regulatory network

Potoyan

Zheng

Komives³

et al. 2015

Preprint

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“…Most of the successful CG models use from 2 (oxDNA [135][136][137][138], and Aksim nti v's m d l [148]), or 3 (3SPN [131][132][133]139,140], BioModi [149]), to eight beads per nucleotide (see Figure 2, and Table 1 for more details). However, coarser models with five beads per base-pair step (four nucleotides), or even a single bead per nucleotide have emerged [126,127].…”

Section: Coarse-grain Studiesmentioning

confidence: 99%

“…In this regard, several coarse-grained models were applied to understand certain processes of biological interest, like duplex formation starting from short ssDNA oligomers [127,131,132,142]. Other models have shown to be useful in reproducing the structure of DNA/RNA duplexes [129], or structural properties such as the sequencedependent/salt-dependent persistence length [127,131,132], or the DNA curvature. The model from Vercauteren and coworkers was able to reproduce the topology of several DNA mini-circles with different link numbers, simulated using explicit K + Cl -ions [126].…”

Section: Coarse-grain Studiesmentioning

confidence: 99%

Multiscale simulation of DNA

Dans¹,

Walther

Gómez

et al. 2016

Current Opinion in Structural Biology

142

131

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DNA is not only among the most important molecules in life, but a meeting point for biology, physics and chemistry, being studied by numerous techniques. Theoretical methods can help in gaining a detailed understanding of DNA structure and function, but their practical use is hampered by the multiscale nature of this molecule. In this regard, the study of DNA covers a broad range of different topics, from sub-Angstrom details of the electronic distributions of nucleobases, to the mechanical properties of millimeter-long chromatin fibers. Some of the biological processes involving DNA occur in femtoseconds, while others require years. In this review, we describe the most recent theoretical methods that have been considered to study DNA, from the electron to the chromosome, enriching our knowledge on this fascinating molecule.

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Coarse-grained modeling of DNA curvature

Cited by 125 publications

References 38 publications

Molecular stripping in the NF-κB/IκB/DNA genetic regulatory network

Molecular stripping in the NF-κB/IκB/DNA genetic regulatory network

Molecular stripping in the NFκB/IκB/DNA genetic regulatory network

Multiscale simulation of DNA

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