Acto-Myosin Contractility Regulates Nuclear and Chromatin Plasticity (original) (raw)
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Force field parameters for the simulation of modified histone tails
Journal of Computational Chemistry, 2010
We describe the development of force field parameters for methylated lysines and arginines, and acetylated lysine for the CHARMM all-atom force field. We also describe a CHARMM united-atom force field for modified sidechains suitable for use with fragment-based docking methods. The development of these parameters is based on results of ab initio quantum mechanics calculations of model compounds with subsequent refinement and validation by molecular mechanics and molecular dynamics simulations. The united-atom parameters are tested by fragment docking to target proteins using the MCSS procedure. The all-atom force field is validated by molecular dynamics simulations of multiple experimental structures. In both sets of calculations, the computational predictions using the force field were compared to the corresponding experimental structures. We show that the parameters yield an accurate reproduction of experimental structures. Together with the existing CHARMM force field, these parameters will enable the general modeling of post-translational modifications of histone tails.
Biopolymers, 2014
The positively charged N-terminal histone tails play a crucial role in chromatin compaction and are important modulators of DNA transcription, recombination, and repair. The detailed mechanism of the interaction of histone tails with DNA remains elusive. To model the unspecific interaction of histone tails with DNA, all-atom molecular dynamics (MD) simulations were carried out for systems of four DNA 22-mers in the presence of 20 or 16 short fragments of the H4 histone tail (variations of the 16-23 a. a. KRHRKVLR sequence, as well as the unmodified fragment a. a.13-20, GGAKRHRK). This setup with high DNA concentration, explicit presence of DNA-DNA contacts, presence of unstructured cationic peptides (histone tails) and K 1 mimics the conditions of eukaryotic chromatin. A detailed account of the DNA interactions with the histone tail fragments, K 1 and water is presented. Furthermore, DNA structure and dynamics and its interplay with the histone tail fragments binding are analysed. The charged side chains of the lysines and arginines play major roles in the tailmediated DNA-DNA attraction by forming bridges and by coordinating to the phosphate groups and to the electronegative sites in the minor groove. Binding of all species to DNA is dynamic. The structure of the unmodified fully-charged H4 16-23 a.a. fragment KRHRKVLR is dominated by a stretched conformation. The H4 tail a. a. fragment GGAKRHRK as well as the H4 Lys16 acetylated fragment are highly flexible. The present work allows capturing typical features of the histone tail-counterion-DNA structure, interaction and dynamics. V
The role of histone tails in nucleosome stability: An electrostatic perspective
Computational and Structural Biotechnology Journal, 2020
We propose a methodology for the study of protein-DNA electrostatic interactions and apply it to clarify the effect of histone tails in nucleosomes. This method can be used to correlate electrostatic interactions to structural and functional features of protein-DNA systems, and can be combined with coarse-grained representations. In particular, we focus on the electrostatic field and resulting forces acting on the DNA. We investigate the electrostatic origins of effects such as different stages in DNA unwrapping, nucleosome destabilization upon histone tail truncation, and the role of specific arginines and lysines undergoing Post-Translational Modifications. We find that the positioning of the histone tails can oppose the attractive pull of the histone core, locally deform the DNA, and tune DNA unwrapping. Small conformational variations in the often overlooked H2A C-terminal tails had significant electrostatic repercussions near the DNA entry and exit sites. The H2A N-terminal tail exerts attractive electrostatic forces towards the histone core in positions where Polymerase II halts its progress. We validate our results with comparisons to previous experimental and computational observations.
Flexible Histone Tails in a New Mesoscopic Oligonucleosome Model
Biophysical Journal, 2006
We describe a new mesoscopic model of oligonucleosomes that incorporates flexible histone tails. The nucleosome cores are modeled using the discrete surface-charge optimization model, which treats the nucleosome as an electrostatic surface represented by hundreds of point charges; the linker DNAs are treated using a discrete elastic chain model; and the histone tails are modeled using a bead/chain hydrodynamic approach as chains of connected beads where each bead represents five protein residues. Appropriate charges and force fields are assigned to each histone chain so as to reproduce the electrostatic potential, structure, and dynamics of the corresponding atomistic histone tails at different salt conditions. The dynamics of resulting oligonucleosomes at different sizes and varying salt concentrations are simulated by Brownian dynamics with complete hydrodynamic interactions. The analyses demonstrate that the new mesoscopic model reproduces experimental results better than its predecessors, which modeled histone tails as rigid entities. In particular, our model with flexible histone tails: correctly accounts for salt-dependent conformational changes in the histone tails; yields the experimentally obtained values of histone-tail mediated core/ core attraction energies; and considers the partial shielding of electrostatic repulsion between DNA linkers as a result of the spatial distribution of histone tails. These effects are crucial for regulating chromatin structure but are absent or improperly treated in models with rigid histone tails. The development of this model of oligonucleosomes thus opens new avenues for studying the role of histone tails and their variants in mediating gene expression through modulation of chromatin structure.
ScienceDirect, 2021
The atomic interactions between histone molecule and 3LPT protein are reported using the molecular dynamics (MD) method in this computational work. This computational study is done for the first time. The results of the MD simulations on the dynamical manner of these structures have been reported by calculating various physical parameters. Physically, our results show that the attraction forces between the histone molecule and 3LPT protein destructed the 3LPT protein after 2 ns. Further, the temperature and pressure of these structures are important parameters in their atomic interactions. Numerically, by increasing these two parameters from 300 K to 350 K and 0 to 1 bar, respectively, the interatomic distance between these structures decreases from 7 Å to 2.54 Å and 7 Å to 2.79 Å (respectively). Further, bonding energy in these simulations varies from 23.51 eV to 31.78 eV. The diffusion coefficient of histone structure into 3LPT protein is another important parameter. Numerically , this physical coefficient changes from 0.58μm 2 /s to 0.89 μm 2 /s.
Role of Histone Tails in Structural Stability of the Nucleosome
PLoS Computational Biology, 2011
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 a-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 H2Aa3 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.
2023
Full-length histone tails play a well characterized role in nucleosome core particles, and, as intrinsically disordered peptides, represent a current challenge for all-atom molecular dynamics simulations. Beyond the choice of the force field, the folding and the subsequent interactions with DNA landscape is complex and calls for a robust computational protocol capable of reproducibility. In this contribution, we assessed by a specifically tailored REST2-based simulation protocol the interaction between the four canonical histone tails and a DNA fragment from a canonical nucleosome core particles. We report contact maps obtained by clustering along several microseconds which prefigure plausible interactions between some of the positively-charged residues and DNA. Two major post-translational modifications of lysines are also discussed. Our work thus contributes to pave the way toward 1
Multiscale Modeling of Nucleosome Dynamics
Biophysical Journal, 2007
Nucleosomes form the fundamental building blocks of chromatin. Subtle modifications of the constituent histone tails mediate chromatin stability and regulate gene expression. For this reason, it is important to understand structural dynamics of nucleosomes at atomic levels. We report a novel multiscale model of the fundamental chromatin unit, a nucleosome, using a simplified model for rapid discrete molecular dynamics simulations and an all-atom model for detailed structural investigation. Using a simplified structural model, we perform equilibrium simulations of a single nucleosome at various temperatures. We further reconstruct all-atom nucleosome structures from simulation trajectories. We find that histone tails bind to nucleosomal DNA via strong salt-bridge interactions over a wide range of temperatures, suggesting a mechanism of chromatin structural organization whereby histone tails regulate inter-and intranucleosomal assemblies via binding with nucleosomal DNA. We identify specific regions of the histone core H2A/H2B-H4/H3-H3/H4-H2B/H2A, termed ''cold sites'', which retain a significant fraction of contacts with adjoining residues throughout the simulation, indicating their functional role in nucleosome organization. Cold sites are clustered around H3-H3, H2A-H4 and H4-H2A interhistone interfaces, indicating the necessity of these contacts for nucleosome stability. Essential dynamics analysis of simulation trajectories shows that bending across the H3-H3 is a prominent mode of intranucleosomal dynamics. We postulate that effects of salts on mononucleosomes can be modeled in discrete molecular dynamics by modulating histone-DNA interaction potentials. Local fluctuations in nucleosomal DNA vary significantly along the DNA sequence, suggesting that only a fraction of histone-DNA contacts make strong interactions dominating mononucleosomal dynamics. Our findings suggest that histone tails have a direct functional role in stabilizing higher-order chromatin structure, mediated by salt-bridge interactions with adjacent DNA.
Biophysical Journal, 2009
Coarse-grained Langevin molecular dynamics computer simulations were conducted for systems that mimic solutions of nucleosome core particles (NCPs). The NCP was modeled as a negatively charged spherical particle representing the complex of DNA and the globular part of the histones combined with attached strings of connected charged beads modeling the histone tails. The size, charge, and distribution of the tails relative to the core were built to match real NCPs. Three models of NCPs were constructed to represent different extents of covalent modification on the histone tails: (nonmodified) recombinant (rNCP), acetylated (aNCP), and acetylated and phosphorylated (paNCP). The simulation cell contained 10 NCPs in a dielectric continuum with explicit mobile counterions and added salt. The NCP-NCP interaction is decisively dependent on the modification state of the histone tails and on salt conditions. Increasing the monovalent salt concentration (KCl) from salt-free to physiological concentration leads to NCP aggregation in solution for rNCP, whereas NCP associates are observed only occasionally in the system of aNCPs. In the presence of divalent salt (Mg 2þ), rNCPs form dense stable aggregates, whereas aNCPs form aggregates less frequently. Aggregates are formed via histone-tail bridging and accumulation of counterions in the regions of NCP-NCP contacts. The paNCPs do not show NCP-NCP interaction upon addition of KCl or in the presence of Mg 2þ. Simulations for systems with a gradual substitution of K þ for Mg 2þ , to mimic the Mg 2þ titration of an NCP solution, were performed. The rNCP system showed stronger aggregation that occurred at lower concentrations of added Mg 2þ , compared to the aNCP system. Additional molecular dynamics simulations performed with a single NCP in the simulation cell showed that detachment of the tails from the NCP core was modest under a wide range of salt concentrations. This implies that salt-induced tail dissociation of the histone tails from the globular NCP is not in itself a major factor in NCP-NCP aggregation. The approximation of coarse-graining, with respect to the description of the NCP as a sphere with uniform charge distribution, was tested in control simulations. A more detailed description of the NCP did not change the main features of the results. Overall, the results of this work are in agreement with experimental data reported for NCP solutions and for chromatin arrays.
Modelling protein-DNA interactions in chromatin
fz-juelich.de
Proteins with positive charges strongly interact with DNA and, in the important cases of histones and histone-like proteins, they pack and bend long segments of DNA into highly ordered structures . In this contribution we report the results of combining numerical simulations in generalized ensembles (modulated metastatistics) with polyelectrolyte theory. The example of the interaction between the N-terminal tail of the H3 histone with segments of DNA will be illustrated, to explain the role of histone charged tails in the compaction of the genetic code in eukaryotic cells.