Price of disorder in the lac repressor hinge helix

Seckfort, Danielle; Pettitt, B. Montgomery

doi:10.1002/bip.23239

Cited by 4 publications

(2 citation statements)

References 103 publications

(152 reference statements)

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“…A small residue fragment adjacent to the DBD, known as the helical hinge domain (residues ≈50−58) inserts into the DNA minor groove, lending additional stability. Given its small size, this complex has been extensively studied using molecular dynamics simulations 16,41,115,116 to infer details of DNA− protein binding specificity in the context of transcription regulation. We initiated simulations at 315 K using the coordinates of the NMR-derived structure deposited in the PDB database (PDB ID: 1L1M).…”

Section: Journal Of Chemicalmentioning

confidence: 99%

Brewing COFFEE: A Sequence-Specific Coarse-Grained Energy Function for Simulations of DNA−Protein Complexes

Chakraborty,

Mondal,

Thirumalai

2024

J. Chem. Theory Comput.

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DNA−protein interactions are pervasive in a number of biophysical processes ranging from transcription and gene expression to chromosome folding. To describe the structural and dynamic properties underlying these processes accurately, it is important to create transferable computational models. Toward this end, we introduce Coarse-grained Force Field for Energy Estimation, COFFEE, a robust framework for simulating DNA− protein complexes. To brew COFFEE, we integrated the energy function in the self-organized polymer model with side-chains for proteins and the three interaction site model for DNA in a modular fashion, without recalibrating any of the parameters in the original force-fields. A unique feature of COFFEE is that it describes sequence−specific DNA−protein interactions using a statistical potential (SP) derived from a data set of high-resolution crystal structures. The only parameter in COFFEE is the strength (λ DNAPRO ) of the DNA−protein contact potential. For an optimal choice of λ DNAPRO , the crystallographic B-factors for DNA−protein complexes with varying sizes and topologies are quantitatively reproduced. Without any further readjustments to the force-field parameters, COFFEE predicts scattering profiles that are in quantitative agreement with small-angle X-ray scattering experiments, as well as chemical shifts that are consistent with NMR. We also show that COFFEE accurately describes the salt-induced unraveling of nucleosomes. Strikingly, our nucleosome simulations explain the destabilization effect of ARG to LYS mutations, which do not alter the balance of electrostatic interactions but affect chemical interactions in subtle ways. The range of applications attests to the transferability of COFFEE, and we anticipate that it would be a promising framework for simulating DNA−protein complexes at the molecular length-scale.

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Section: Journal Of Chemicalmentioning

confidence: 99%

Brewing COFFEE: A Sequence-Specific Coarse-Grained Energy Function for Simulations of DNA−Protein Complexes

Chakraborty,

Mondal,

Thirumalai

2024

J. Chem. Theory Comput.

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show abstract

“…A small residue fragment adjacent to the DBD, known as the helical hinge domain (residues ≈ 50-58) inserts into the DNA minor groove, lending additional stability. Given its small size, this complex has been extensively studied using molecular dynamics simulations 37,[103][104][105] to infer details of DNA-protein binding specificity in the context of transcription regulation.…”

Section: Residuesmentioning

confidence: 99%

Brewing COFFEE: A sequence-specific coarse-grained energy function for simulations of DNA-protein complexes

Chakraborty

Mondal

Thirumalai

2023

Preprint

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DNA-protein interactions are pervasive in a number of biophysical processes ranging from transcription, gene expression, chromosome folding. To describe the structural and dynamic properties underlying these processes accurately, it is important to create transferable computational models. Toward this end we introduce Coarse grained force field for energy estimation, COFFEE, a robust framework for simulating DNA-protein complexes. To brew COFFEE, we integrated the energy function in the Self-Organized Polymer model with Side Chains for proteins and the Three Interaction Site model for DNA in a modular fashion, without re-calibrating any of the parameters in the original force fields. A unique feature of COFFEE is that it describes sequence-specific DNA-protein interactions using a statistical potential (SP) derived from a dataset of high-resolution crystal structures. The only parameter in COFFEE is the strength (λDNAPRO) of the DNA-protein contact potential. For an optimal choice of λDNAPRO, the crystallographic B-factors for DNA-protein complexes, with varying sizes and topologies, are quantitatively reproduced. Without any further readjustments to the force-field parameters, COFFEE predicts the scattering profiles that are in quantitative agreement with SAXS experiments as well as chemical shifts that are consistent with NMR. We also show that COFFEE accurately describes the salt-induced unraveling of nucleosomes. Strikingly, our nucleosome simulations explain the destabilization effect of ARG to LYS mutations, which does not alter the balance of electrostatic interactions, but affects chemical interactions in subtle ways. The range of applications attests to the transferability of COFFEE, and we anticipate that it is a promising framework for simulating DNA-protein complexes at the molecular length-scale.

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The lac repressor hinge helix in context: The effect of the DNA binding domain and symmetry

Seckfort

Lynch

Pettitt

2020

Biochimica et Biophysica Acta (BBA) - General Subjects

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Price of disorder in the lac repressor hinge helix

Cited by 4 publications

References 103 publications

Brewing COFFEE: A Sequence-Specific Coarse-Grained Energy Function for Simulations of DNA−Protein Complexes

Brewing COFFEE: A Sequence-Specific Coarse-Grained Energy Function for Simulations of DNA−Protein Complexes

Brewing COFFEE: A sequence-specific coarse-grained energy function for simulations of DNA-protein complexes

The lac repressor hinge helix in context: The effect of the DNA binding domain and symmetry

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