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.2016 May 6;11(5):e0155105.
doi: 10.1371/journal.pone.0155105. eCollection 2016.

Investigations of the CLOCK and BMAL1 Proteins Binding to DNA: A Molecular Dynamics Simulation Study

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Investigations of the CLOCK and BMAL1 Proteins Binding to DNA: A Molecular Dynamics Simulation Study

Tuo Xue et al. PLoS One..

Abstract

The circadian locomotor output cycles kaput (CLOCK), and brain and muscle ARNT-like 1 (BMAL1) proteins are important transcriptional factors of the endogenous circadian clock. The CLOCK and BMAL1 proteins can regulate the transcription-translation activities of the clock-related genes through the DNA binding. The hetero-/homo-dimerization and DNA combination of the CLOCK and BMAL1 proteins play a key role in the positive and negative transcriptional feedback processes. In the present work, we constructed a series of binary and ternary models for the bHLH/bHLH-PAS domains of the CLOCK and BMAL1 proteins, and the DNA molecule, and carried out molecular dynamics simulations, free energy calculations and conformational analysis to explore the interaction properties of the CLOCK and BMAL1 proteins with DNA. The results show that the bHLH domains of CLOCK and BMAL1 can favorably form the heterodimer of the bHLH domains of CLOCK and BMAL1 and the homodimer of the bHLH domains of BMAL1. And both dimers could respectively bind to DNA at its H1-H1 interface. The DNA bindings of the H1 helices in the hetero- and homo-bHLH dimers present the rectangular and diagonal binding modes, respectively. Due to the function of the α-helical forceps in these dimers, the tight gripping of the H1 helices to the major groove of DNA would cause the decrease of interactions at the H1-H2 interfaces in the CLOCK and BMAL1 proteins. The additional PAS domains in the CLOCK and BMAL1 proteins affect insignificantly the interactions of the CLOCK and BMAL1 proteins with the DNA molecule due to the flexible and long loop linkers located at the middle of the PAS and bHLH domains. The present work theoretically explains the interaction mechanisms of the bHLH domains of the CLOCK and BMAL1 proteins with DNA.

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Conflict of interest statement

Competing Interests:The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Compositions of the bHLH-PAS domain of CLOCK/BMAL1 protein, and DNA.
The amino acid extremities and the domain organization of the bHLH-PAS domains of the CLOCK and BMAL1 proteins, and the base sequence of DNA.
Fig 2
Fig 2. RMSD values of the binary and phosphorylated models.
RMSD values of all heavy atoms with respect to the corresponding starting structures for MD simulations of (a) the CbHLH+BbHLH, BbHLH+BbHLH and CbHLH+CbHLH models, and (b) the CbHLH+BPhos+DNA and BPhos+BPhos+DNA models.
Fig 3
Fig 3. Structures of three models for the CLOCK and BMAL1 proteins, and DNA.
Average simulated structures for (a) the CbHLH+BbHLH model, (b) the CbHLH+BbHLH+DNA model, and (c) the CbHLH+BbHLH+PAS+DNA model.
Fig 4
Fig 4. The electrostatic surface potentials of the CbHLH+BbHLH+DNA model.
The electrostatic surface potentials for the bHLH domains of the CLOCK and BMAL1 proteins, and for the DNA molecule in the CbHLH+BbHLH+DNA model.
Fig 5
Fig 5. The fluctuations of residues and bases in the CbHLH+BbHLH and CbHLH+BbHLH+DNA models.
The fluctuations of residues and bases in the CbHLH+BbHLH (light magenta) and CbHLH+BbHLH+DNA (red) models.
Fig 6
Fig 6. Motion correlations, eigenvector map and differences of the protein motion correlations of the CbHLH+BbHLH and CbHLH+BbHLH+DNA models.
(a) Motion correlations of the CbHLH+BbHLH+DNA model with the key subregions of CLOCK and BMAL1 squared in blue and green, respectively. (b) Eigenvector map of the corresponding matrix with the first three larger eigenvalues in the CbHLH+BbHLH+DNA model. The blue, green and black squares in (b) presented the same meaning in (a). (c) The differences of the protein motion correlations from the CbHLH+BbHLH to CbHLH+BbHLH+DNA models with the specific subregions squared in black.
Fig 7
Fig 7. Energy decompositions of the CbHLH+BbHLH+DNA and CbHLH+BPhos+DNA models.
MM-PBSA energy decompositions (kcal·mol-1) into the residues of the bHLH domains and the bases of the DNA molecule for the CbHLH+BbHLH+DNA (red) and CbHLH+BPhos+DNA (sky blue) models.
Fig 8
Fig 8. Conformation differences of the CbHLH+BbHLH+DNA and CbHLH+BPhos+DNA models.
(a) The conformational difference of the H1B helix, (b) the different electrostatic surface potentials of the residue of Ser78/Ser(PO3)78, and (c) the different positions of the key residues in the CbHLH+BbHLH+DNA (red) and CbHLH+BPhos+DNA (sky blue) models.
Fig 9
Fig 9. Charged residues in the binary models.
Some positive-charged residues (blue polyhedron) and the negative-charged residues (red polyhedron) at the H1-H2 interfaces in the CbHLH+BbHLH model ((a) and (b)), the BbHLH+BbHLH model (c), and the CbHLH+CbHLH model (d)
Fig 10
Fig 10. The helical distances in the binary models.
The helical distances (Å) between the H1 and H2 helices in the CbHLH+BbHLH (red), BbHLH+BbHLH (green), and CbHLH+CbHLH (blue) models.
Fig 11
Fig 11. The interhelical angles and the distances of the CbHLH+BbHLH+DNA and BbHLH+BbHLH+DNA models.
(a) The interhelical angles (°) between the H1 helices, and (b) the distances (Å) between the C atoms for Ile80 in the H1 helix of BMAL1 and T20 in DNA in the CbHLH+BbHLH+DNA (red) and BbHLH+BbHLH+DNA (green) models.
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The authors acknowledge research support from the National Science Foundation of China (Nos. 21271029, 21131003, 21073015, and 21573020), and the Major State Basic Research Development Programs (Grant No. 2011CB808500).

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