Explicit ion modeling predicts physicochemical interactions for chromatin organization
- Department of Chemistry, Massachusetts Institute of Technology, United States
Figures
Figure 1
Illustration of the residue-level coarse-grained explicit ion model for chromatin simulations.
The left panel presents a snapshot for the simulation box of a 147 bp nucleosome in a solution of 100 mM NaCl and 0.5 mM MgCl2. The nucleosomal DNA and histone proteins are colored in red and white, …
Figure 2 with 1 supplement
Explicit ion modeling reproduces the energetics of nucleosomal DNA unwrapping.
(A) Illustration of the umbrella simulation setup using the end-to-end distance between two DNA termini as the collective variable. The same color scheme as in Figure 1 is adopted. Only ions close …
Figure 2—figure supplement 1
The explicit ion model predicts the binding affinities of protein-DNA complexes well, related to Figure 1 of the main text.
Experimental and simulated binding free energies are compared for nine protein-DNA complexes (Privalov et al., 2011), with a Pearson correlation coefficient of 0.6. The PDB ID for each complex is …
Figure 3 with 1 supplement
Explicit ion modeling predicts salt-dependent conformations of a 12-mer nucleosome array.
(A) Top: Comparison of simulated and experimental (Correll et al., 2012) sedimentation coefficients of chromatin at different salt concentrations. Bottom: Number of DNA charges neutralized by bound …
Figure 3—figure supplement 1
Probability distributions used to compute means and standard deviations of the quantities presented in Figure 3 of the main text.
(A) Probability distribution of sedimentation coefficients calculated from the simulation with Na+ ions. (B) Probability distribution of sedimentation coefficients calculated from the simulation …
Figure 4 with 4 supplements
Close contacts give rise to strong inter-nucleosomal interactions.
(A) Illustration of the simulation protocol employed to mimic the nucleosome unbinding pathway dictated by the DNA-origami device (Funke et al., 2016). The three configurations, A1, A2, and A3, …
Figure 4—figure supplement 1
Illustration of the restrained two nucleosome simulations setup, related to Figure 4 of the main text.
(A) Schematics of the DNA-origami-based force spectrometer, reproduced from Figure 1 of Funke et al., 2016. (B) Schematics for the spatial restraints imposed on nucleosomes in our simulations to …
Figure 4—figure supplement 2
Explicit ion modeling reproduces the experimental free energy profiles of nucleosome binding.
(A) Comparison between the simulated (black) and experimental (red) free energy profile as a function of the inter-nucleosome distance. Error bars were computed as the standard deviation of three …
Figure 4—figure supplement 3
Compared with DNA-origami-restrained simulations, the unrestrained simulations produce more histone-DNA contacts across nucleosomes, related to Figure 4 of the main text.
The average number of inter-nucleosome contacts between DNA and histone tails (A) or histone cores (B) is plotted as a function of the distance . The error bars were estimated as the standard …
Figure 4—figure supplement 4
The unrestricted simulations favor a smaller angle between two nucleosomal planes compared to the DNA-origami-restrained simulations, related to Figure 4 of the main text.
(A) Illustration of the collective variables used in the umbrella-sampling simulation. is the angle between two nucleosomal planes, and is the distance between the geometric centers of two …
Figure 5 with 3 supplements
Simulations predict significant inter-nucleosome interactions at physiological conditions.
(A) Illustration of the collective variable, , defined as the angle between two nucleosomal planes, and defined as the distance between the nucleosome geometric centers. and represent the …
Figure 5—figure supplement 1
Dependence of inter-nucleosome interactions on the DNA sequence, related to Figure 5 of the main text.
See text section ‘Simulations at the physiological salt concentration’ for further discussions on simulation details. (A) Illustration of the collective variables used in umbrella-sampling …
Figure 5—figure supplement 2
The poly-dA:dT sequence produces a higher number of cross-nucleosome histone-DNA contacts compared to the poly-dG:dC sequence, related to Figure 5 of the main text.
(A) The average number of inter-nucleosome contacts between histone proteins and nucleosomal DNA is plotted as a function of the distance between the geometric centers of two nucleosomes. The …
Figure 5—figure supplement 3
Free energy profiles for the interactions between a pair of nucleosomes at different nucleosome repeat lengths (NRL) and in the presence of the linker histone H1.0, related to Figure 5 of the main text.
See text section ‘Simulations at the physiological salt concentration’ for further discussions on simulation details. (A) Illustration of the collective variables used in the umbrella-sampling …
Appendix 1—figure 1
A cutoff value of 8.0 Å produces more accurate values for the number of unwrapped DNA base pairs as determined from visual inspection of representative configurations, related to Figure 2 of the main text.
See text section ‘Number of unwrapped DNA base pairs’ for additional discussions. A typical nucleosome structure with most of the outer layer DNA unwrapped was used to examine the impact of …
Author response image 1
Comparison between the radial distribution functions of Na+ (left) and Mg2+ (right) ions around the DNA phosphate groups computed from all-atom (black) and coarse-grained (red) simulations.
Figure reproduced from Figure 4 of [1]. The coarse-grained explicit ion model used in producing the red curves is identical to the one presented in the current manuscript.
© 2011, AIP Publishing. This figure is reproduced with permission from Figure 4 in Freeman GS, Hinckley DM, de Pablo JJ (2011) A coarse-grain three-site-pernucleotide model for DNA with explicit ions. The Journal of Chemical Physics 135:165104. It is not covered by the CC-BY 4.0 license and further reproduction of this figure would need permission from the copyright holder.
Author response image 2
Three-dimensional distribution of sodium ions around the nucleosome determined from all-atom explicit solvent simulations.
Darker blue colors indicate higher sodium density and high density of sodium ions around the DNA is clearly visible. The crystallographically identified acidic patch has been highlighted as spheres …
Author response image 3
Time trace of the radius of gyration (Rg) of a nucleosome with the 601-sequence along an unbiased, equilibrium trajectory.
It is evident the Rg fluctuates around the value found in the PDB structure (3.95 nm), supporting the stability of the nucleosome in our simulation.
Author response image 4
The explicit-ion model predicts the binding affinities of protein-DNA complexes well, related to Fig.
1 of the main text. Experimental and simulated binding free energies are compared for nine protein-DNA complexes [cite], with a Pearson Correlation coefficient of 0.6. The PDB ID for each complex is …
Author response image 5
Revised main text Figure 5, with Figure 5D modified for improved visual clarity.
Author response image 6
Explicit ion modeling reproduces the experimental free energy profiles of nucleosome binding.
(A) Comparison between the simulated (black) and experimental (red) free energy profile as a function of the inter-nucleosome distance. Error bars were computed as the standard deviation of three …
Tables
Table 1
Summary of parameters used to describe interactions between ions and charged particles.
See text section ‘Coarse-grained explicit ion model’ for definitions of various parameters.
| Coarse-grained pair | (kcal/mol) | (Å) | (Å) | (Å) | (kcal/mol) | (Å) | (Å) | (kcal/mol) | (Å) | (Å) |
|---|---|---|---|---|---|---|---|---|---|---|
| P-P | 0.18379 | 6.86 | 6.86 | 0.5 | – | – | – | – | – | – |
| Na+-P | 0.02510 | 4.14 | 3.44 | 1.25 | 3.15488 | 4.1 | 0.57 | 0.47801 | 6.5 | 0.4 |
| Na+-AA+* | 0.239 | 4.065 | 3.44 | 1.25 | 3.15488 | 4.1 | 0.57 | – | – | – |
| Na+-AA−† | 0.239 | 4.065 | 3.44 | 1.25 | 3.15488 | 4.1 | 0.57 | 0.47801 | 6.5 | 0.4 |
| Mg2+-P | 0.1195 | 4.87 | 3.75 | 1.0 | 1.29063 | 6.1 | 0.5 | 0.97992 | 8.3 | 1.2 |
| Mg2+-AA+ | 0.239 | 3.556 | 3.75 | 1.0 | 1.29063 | 6.1 | 0.5 | – | – | – |
| Mg2+-AA− | 0.239 | 3.556 | 3.75 | 1.0 | 1.29063 | 6.1 | 0.5 | 0.97992 | 8.3 | 1.2 |
| Cl−-P | 0.08121 | 5.5425 | 4.2 | 0.5 | 0.83652 | 6.7 | 1.5 | – | – | – |
| Cl−-AA+ | 0.239 | 4.8725 | 4.2 | 0.5 | 0.83652 | 6.7 | 1.5 | 0.47801 | 5.6 | 0.4 |
| Cl−-AA− | 0.239 | 4.8725 | 4.2 | 0.5 | 0.83652 | 6.7 | 1.5 | – | – | – |
| Na+-Na+ | 0.01121 | 2.43 | 2.7 | 0.57 | 0.17925 | 5.8 | 0.57 | – | – | – |
| Na+-Mg2+ | 0.04971 | 2.37 | 2.37 | 0.5 | – | – | – | – | – | – |
| Na+-Cl− | 0.08387 | 3.1352 | 3.9 | 2.06 | 5.49713 | 3.3 | 0.57 | 0.47801 | 5.6 | 0.4 |
| Mg2+-Mg2+ | 0.89460 | 1.412 | 1.412 | 0.5 | – | – | – | – | – | – |
| Mg2+-Cl− | 0.49737 | 4.74 | 4.48 | 0.57 | 1.09943 | 5.48 | 0.44 | 0.05975 | 8.16 | 0.35 |
| Cl−-Cl− | 0.03585 | 4.045 | 4.2 | 0.56 | 0.23901 | 6.2 | 0.5 | – | – | – |
-
*
Positive amino acids.
-
†
Negative amino acids.
Table 2
Summary of parameters used to describe the WCA interactions between ions and neutral particles.
See text section ‘Coarse-grained explicit ion model’ for definitions of various parameters.
| Coarse-grained pair | (kcal/mol) | (Å) |
|---|---|---|
| Na+-S* | 0.239 | 4.315 |
| Na+-A† | 0.239 | 3.915 |
| Na+-T‡ | 0.239 | 4.765 |
| Na+-G§ | 0.239 | 3.665 |
| Na+-C¶ | 0.239 | 4.415 |
| Na+-AA** | 0.239 | 4.065 |
| Mg2+-S | 0.239 | 3.806 |
| Mg2+-A | 0.239 | 3.406 |
| Mg2+-T | 0.239 | 4.256 |
| Mg2+-G | 0.239 | 3.156 |
| Mg2+-C | 0.239 | 3.906 |
| Mg2+-AA** | 0.239 | 3.556 |
| Cl−-S | 0.239 | 5.1225 |
| Cl−-A | 0.239 | 4.7225 |
| Cl−-T | 0.239 | 5.5725 |
| Cl−-G | 0.239 | 4.4725 |
| Cl−-C | 0.239 | 5.2225 |
| Cl−-AA** | 0.239 | 4.8725 |
-
*
Sugar.
-
†
Adenine base.
-
‡
Thymine base.
-
§
Guanine base.
-
¶
Cytosine base.
-
**
Non-charged amino acids.
Table 3
Summary of simulation setups used in this study.
Additional simulation details can be found in text section ‘Molecular dynamics simulation details’.
| Studies | Box size (nm3) | Number of Na+ | Number of Mg2+ | Number of Cl− |
|---|---|---|---|---|
| Single nucleosome 100 mM NaCl+0.5 mM MgCl2 | 216,000 | 13,017 | 65 | 13,003 |
| Twelve nucleosomes 5 mM NaCl | 1,331,000 | 6196 | 0 | 4006 |
| Twelve nucleosomes 150 mM NaCl | 216,000 | 21,695 | 0 | 19,505 |
| Twelve nucleosomes 0.6 mM MgCl2 | 3,375,000 | 0 | 2314 | 2438 |
| Twelve nucleosomes 1 mM MgCl2 | 3,375,000 | 0 | 3127 | 4064 |
| Two 147 bp 601-seq nucleosomes 35 mM NaCl+11 mM MgCl2 | 125,000 | 2922 | 828 | 4290 |
| Two 147 bp 601-seq nucleosomes 150 mM NaCl+2 mM MgCl2 | 216,000 | 19,505 | 260 | 19,737 |
| Two 147 bp poly-dA:dT nucleosomes 150 mM NaCl+2 mM MgCl2 | 216,000 | 19,505 | 260 | 19,737 |
| Two 147 bp poly-dG:dC nucleosomes 150 mM NaCl+2 mM MgCl2 | 216,000 | 19,505 | 260 | 19,737 |
| Two 167 bp 601-seq nucleosomes 150 mM NaCl+2 mM MgCl2 | 216,000 | 19,505 | 260 | 19,657 |
| Two 167 bp 601-seq nucleosomes with H1.0 150 mM NaCl+2 mM MgCl2 | 216,000 | 19,505 | 260 | 19,763 |
