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. 2011 Dec;7(12):e1002279.
doi: 10.1371/journal.pcbi.1002279. Epub 2011 Dec 15.

Role of histone tails in structural stability of the nucleosome

Mithun Biswas  1 , Karine Voltz, Jeremy C Smith, Jörg Langowski
Affiliations

Role of histone tails in structural stability of the nucleosome

Mithun Biswas et al. PLoS Comput Biol. 2011 Dec.

Abstract

Histone tails play an important role in nucleosome structure and dynamics. Here we investigate the effect of truncation of histone tails H3, H4, H2A and H2B on nucleosome structure with 100 ns all-atom molecular dynamics simulations. Tail domains of H3 and H2B show propensity of α-helics formation during the intact nucleosome simulation. On truncation of H4 or H2B tails no structural change occurs in histones. However, H3 or H2A tail truncation results in structural alterations in the histone core domain, and in both the cases the structural change occurs in the H2Aα3 domain. We also find that the contacts between the histone H2A C terminal docking domain and surrounding residues are destabilized upon H3 tail truncation. The relation between the present observations and corresponding experiments is discussed.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Architecture of the nucleosome core particle (PDB ID 1KX5; [2]).
The four histone dimers H3, H4, H2A and H2B are colored in blue, green, red and yellow, respectively. The four histone dimers are arranged about a twofold dyad symmetry axis, which also intersects the middle of the DNA fragment. DNA positions around the nucleosome are described by super helical locations, or SHLs, numbered here. The middle of the DNA fragment at the dyad position is referred to as SHL0. Starting from the dyad along the outer wrap of DNA on the nucleosome (shown by an arrow in the figure), each minor groove facing the histone core is denoted by SHLformula image0.5, SHLformula image1.5, etc. (positive in one direction, negative in the other).
Figure 2
Figure 2. Tail domains of the core histone proteins with positions where they were clipped indicated by lines.
In the tail-truncated nucleosome simulations the N-terminal tail domains of H3, H4, H2A and H2B were removed up to residues 26, 17, 11 and 20, respectively. For the H2A tail-truncated simulation the C-terminal residues 118–128 were also removed. Truncation sites for each tail were chosen at known trypsin cleavage sites .
Figure 3
Figure 3. Structural fluctuations in the nucleosome.
(A) Temperature factor of the nucleosome in cartoon representation. The atoms are colored as indicated in the scale. (B) Secondary structure of the histone calculated using the dssp program . During the simulation amino acids 14–20 of H3 (copy 1) and amino acids 11–15 of H2B (copy 1) show propensity to form formula image-helices.
Figure 4
Figure 4. RMSD and order parameter
formula image of histone monomers H3, H4, H2A and H2B. (A) RMSDs for each of the two copies, 1 and 2, of the histone monomer backbone (excluding histone tails) versus simulation time for intact nucleosome. The last frame of the equilibration run was chosen as the reference structure. Trajectory frames were reoriented to the reference structure with least square fitting of backbone atoms (excluding tails). (B) Order parameter formula image of each of the two copies (numbered 1 and 2) of histone monomers H3, H4, H2A and H2B for the four tail-truncated simulations. The reference structures used for RMSD calculations of the truncated and intact nucleosomes were aligned and had zero RMSD. The dotted lines indicate formula image.
Figure 5
Figure 5. Structural changes in histone H2A(2) during tail-truncated simulations.
(A) Structure of histone H2A with position of the formula image domain shown by thickened helix. (B) Upper panel. Order parameter formula image for H2A(2) fold domain from three independent H3 tail-truncated nucleosome simulations. Lower panel. Order parameter formula image for H2A(2)formula image domain from the H3 tail-truncated nucleosome simulation 1. (C) Upper panel. Order parameter formula image for H2A(2) fold domain from two independent H2A tail-truncated nucleosome simulations. Lower panel. Order parameter formula image for H2A(2)formula image domain from the H2A tail-truncated nucleosome simulation 1.
Figure 6
Figure 6. NA backbone and groove characteristics.
(A) Probability distributions for DNA backbone dihedral angles. The dihedral angles formula image(O3'-P-O5'-C5'), formula image(P-O5'-C5'-C4'), formula image(O5'-C5'-C4'-C3'), formula image(C5'-C4'-C3'-O3'), formula image(C4'-C3'-O3'-P) and formula image(C3'-O3'-P-O5') obtained from the intact nucleosome simulation are compared with those from the crystal structure (1KX5.pdb). (B) DNA major and minor groove width fluctuations along the sequence (chain I) in the intact nucleosome simulation. Groove widths are calculated as P-P distances using the algorithm of Hassan and Calladine implemented in 3DNA .
Figure 7
Figure 7. Destabilization of DNA upon tail truncation.
(A) Order parameter formula image for DNA from the four tail-truncated nucleosome simulations. The inset shows the order parameter for the DNA segment between the dyad and SHL +1.5 for the H3 tail-truncated nucleosome simulation. (B) The order parameter formula image for DNA from three independent H3-tail truncated nucleosome simulations.
Figure 8
Figure 8. Interactions with Arg81 of H2A(2) during the intact and H3 tail-truncated simulations.
(A) Number of H-bonds between Arg81 and selected surrounding residues from intact and H3 tail-truncated simulations. The selected surrounding residues are shown in (B) and (C). (B) Arg81 H-bonds with Gln55 and Lys56 of H3(1) and Gly105 and Val107 of H2A(2) during the intact nucleosome simulation. (C) Arg81 H-bonds with DNA in the H3 tail-truncated simulation.
Figure 9
Figure 9. Interactions with Arg88 of H2A(2) during the intact and H3 tail-truncated simulations.
(A) Number of H-bonds between Arg88 and selected surrounding residues from intact and H3 tail-truncated simulations. The selected surrounding residues are shown in (B) and (C). (B) Arg88 H-bonds to Asn94, Gly98 and Val100 of H2A(2) during the intact nucleosome simulation. (C) Arg88 H-bonds to Glu105 of H3(1) and Ala135 of H3(2) in the H3 tail-truncated simulation.
Figure 10
Figure 10. Electrostatic potential maps of DNA and H3 N-terminal tail as seen by Arg81 and Arg88.
Potential is color coded (in units of Volts) as shown in the scale. (A) Snapshot from the intact nucleosome trajectory showing that in presence of the H3 N-terminal tail Arg81 and Arg88 points away from the DNA surface. The location of the formula image-helix in H3 tail is shown in orange ribbons. (B) Snapshot from the H3 tail truncated simulation showing the Arg81 and Arg88 sidechain pointing towards the DNA in the absence of the H3 tail.
Figure 11
Figure 11. Interaction of H2A C terminal extension (amino acids 100–129) with surrounding residues.
(A) Molsurfer generated contact map of H2A C terminal docking domain (amino acids 100–119) interaction surface as derived from interatomic distances calculated from the structure averaged over the 100 ns of the intact nucleosome trajectory. Distances (in units of Å) are color coded as shown in the scale. Residues in close contact with H2A C terminus are indicated. (B) Positions of the H2A C terminal docking domain (colored red) close contact residues are shown in the nucleosome structure. The end of the H2A C terminus (amino acids 120–129) is colored magenta.
Figure 12
Figure 12. Destabilization of H2A docking domain interaction with Ile51, Gln55 and the DNA upon H3 tail truncation.
(A) Interaction energy (vdw+electrostatics) between H2A docking domain and surrounding amino acids (B) Time series of the distance between the centers of mass of Ile51 or Gln55 and the nearest residue on the H2A C terminus (Leu115 and Asn110, respectively) is plotted. (C) Destabilization of H2A C terminus interaction with DNA upon H3 tail truncation. Time series of the minimum distance between Lys118 and Lys119 of H2A C terminus and the DNA is plotted. An increase of the distance between the C terminus end (Lys118 and Lys119) and DNA was considered to be a detachment if the minimum atomic distance between them during a tail-truncated simulation was greater than the minimum distance averaged over the intact nucleosome trajectory plus its standard deviation. The black line (dotted) indicates the minimum distance between C terminus and the DNA (formula image Å) below which the C terminus is ‘in contact’ with the DNA.
Figure 13
Figure 13. Interaction of close contact residues from Fig. 11 , located near the region where H2A C terminus contacts the dyad, for intact and truncated H2A simulations.
The minimum distances between any atom of Lys44, Ile51 or Gln55 and the closest residue on the H2A C terminus (Leu116, Leu115 and Asn110, respectively) are plotted as a function of time. The white line (dotted) indicates the distance (3 formula image) below which residues can be regarded to be in close contact.
Figure 14
Figure 14. Regulation of nucleosome stability through H2A docking domain contacts.
(A) Positions of the H2A–H2B dimer and H3–H4 tetramer in a nucleosome illustrating that the interaction surface between the H2A–H2B dimer and H3–H4 tetramer is provided by the H2A C terminal tail. Histone dimers H3, H4, H2A and H2B are colored in blue, green, red and yellow, respectively. Part of the nucleosome structure is shown in cartoon representation for clarity of vision. (B)–(C) Disruption of contacts between the H3 tail formula image-helix (colored orange) and the DNA triggers change of interaction of histone arginines (Arg81 and Arg88). Newly formed polar contacts between Arg88, Glu105 and Gln112 destabilizes interaction of the H2A docking domain with closely lying amino acids (Ile51 and Gln55). Histone protein domains are shown as ribbons and DNA phosphorous atoms are shown as spheres. Histone domains are color coded as follows : H3formula imageN (blue), H2Aformula image3 (magenta), H2Aformula imageC (grey), H2A docking domain (red).
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