| 1. |
- Berezhnoy, Nikolay V., et al.
(författare)
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Supramolecular Organization in Self-Assembly of Chromatin and Cationic Lipid Bilayers is Controlled by Membrane Charge Density
- 2012
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Ingår i: Biomacromolecules. - : American Chemical Society (ACS). - 1526-4602 .- 1525-7797. ; 13:12, s. 4146-4157
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Tidskriftsartikel (refereegranskat)abstract
- In this work we have investigated the structures of aggregates formed in model systems of dilute aqueous mixtures of "model chromatin" consisting of either recombinant nucleosome core particles (NCPs) or nucleosome arrays consisting of 12 NCPs connected with 30 bp linker DNA, and liposomes made from different mixtures of cationic and zwitterionic lipids, 1,2-dioleoyl-3-trimethylammonium-propane chloride salt (DOTAP) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). The aggregates formed were characterized using different optical microscopy methods and small-angle X-ray scattering (SAXS), and the results are discussed in terms of the competing intermolecular interactions among the components. For a majority of the samples, the presence of lamellar structures could be identified. Ir. samples with high fractions of DOTAP in the liposomes, well-defined lamellar structures very similar to those formed by the corresponding lipid mixtures and DNA alone (i.e., without histone proteins) were observed; in these aggregates, the histones are expelled from the model chromatin. The findings suggest that, with liposomes containing large fractions of cationic lipid, the dominating driving force for aggregation is the increase in translational entropy from the release of counterions, whereas with lower fractions of the cationic lipid, the entropy of mixing of the lipids within the bilayers results in a decreased DNA-lipid attraction.
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| 2. |
- Lundberg, Dan, et al.
(författare)
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Interactions between Cationic Lipid Bilayers and Model Chromatin
- 2010
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Ingår i: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 26:15, s. 12488-12492
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Tidskriftsartikel (refereegranskat)abstract
- Complexes formed in mixtures of cationic liposomes of varying charge density and nucleosome core particles (NCPs) or nucleosome arrays have been characterized. Under most of the conditions studied, the lipids and NCPs or arrays formed lamellar structures similar to those obtained with the liposomes and pure DNA. Thus, the dissociation of DNA from the NCP or nucleosome array and the formation of a DNA-lipid complex is thermodynamically favored, which can likely be ascribed mainly to the gain in entropy on release of the small counterions. Only at very low liposome charge densities are there indications that the NCPs/arrays do not dissociate upon interaction with the lipid bilayers. The reported results can serve as a valuable reference point in investigations of biologically more relevant systems.
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| 3. |
- Fan, Yanping, et al.
(författare)
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An Advanced Coarse-Grained Nucleosome Core Particle Model for Computer Simulations of Nucleosome-Nucleosome Interactions under Varying Ionic Conditions
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:2
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Tidskriftsartikel (refereegranskat)abstract
- In the eukaryotic cell nucleus, DNA exists as chromatin, a compact but dynamic complex with histone proteins. The first level of DNA organization is the linear array of nucleosome core particles (NCPs). The NCP is a well-defined complex of 147 bp DNA with an octamer of histones. Interactions between NCPs are of paramount importance for higher levels of chromatin compaction. The polyelectrolyte nature of the NCP implies that nucleosome-nucleosome interactions must exhibit a great influence from both the ionic environment as well as the positively charged and highly flexible N-terminal histone tails, protruding out from the NCP. The large size of the system precludes a modelling analysis of chromatin at an all-atom level and calls for coarse-grained approximations. Here, a model of the NCP that include the globular histone core and the flexible histone tails described by one particle per each amino acid and taking into account their net charge is proposed. DNA wrapped around the histone core was approximated at the level of two base pairs represented by one bead (bases and sugar) plus four beads of charged phosphate groups. Computer simulations, using a Langevin thermostat, in a dielectric continuum with explicit monovalent (K+), divalent (Mg2+) or trivalent (Co(NH3)(6)(3+)) cations were performed for systems with one or ten NCPs. Increase of the counterion charge results in a switch from repulsive NCP-NCP interaction in the presence of K+, to partial aggregation with Mg2+ and to strong mutual attraction of all 10 NCPs in the presence of CoHex(3+). The new model reproduced experimental results and the structure of the NCP-NCP contacts is in agreement with available data. Cation screening, ion-ion correlations and tail bridging contribute to the NCP-NCP attraction and the new NCP model accounts for these interactions.
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| 4. |
- Korolev, Nikolay, et al.
(författare)
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A Coarse-Grained DNA Model Parameterized from Atomistic Simulations by Inverse Monte Carlo
- 2014
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Ingår i: Polymers. - : MDPI AG. - 2073-4360. ; 6:6, s. 1655-1675
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Tidskriftsartikel (refereegranskat)abstract
- Computer modeling of very large biomolecular systems, such as long DNA polyelectrolytes or protein-DNA complex-like chromatin cannot reach all-atom resolution in a foreseeable future and this necessitates the development of coarse-grained (CG) approximations. DNA is both highly charged and mechanically rigid semi-flexible polymer and adequate DNA modeling requires a correct description of both its structural stiffness and salt-dependent electrostatic forces. Here, we present a novel CG model of DNA that approximates the DNA polymer as a chain of 5-bead units. Each unit represents two DNA base pairs with one central bead for bases and pentose moieties and four others for phosphate groups. Charges, intra-and inter-molecular force field potentials for the CG DNA model were calculated using the inverse Monte Carlo method from all atom molecular dynamic (MD) simulations of 22 bp DNA oligonucleotides. The CG model was tested by performing dielectric continuum Langevin MD simulations of a 200 bp double helix DNA in solutions of monovalent salt with explicit ions. Excellent agreement with experimental data was obtained for the dependence of the DNA persistent length on salt concentration in the range 0.1-100 mM. The new CG DNA model is suitable for modeling various biomolecular systems with adequate description of electrostatic and mechanical properties.
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| 5. |
- Korolev, Nikolay, et al.
(författare)
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A systematic analysis of nucleosome core particle and nucleosome-nucleosome stacking structure
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Chromatin condensation is driven by the energetically favourable interaction between nucleosome core particles (NCPs). The close NCP-NCP contact, stacking, is a primary structural element of all condensed states of chromatin in vitro and in vivo. However, the molecular structure of stacked nucleosomes as well as the nature of the interactions involved in its formation have not yet been systematically studied. Here we undertake an investigation of both the structural and physico-chemical features of NCP structure and the NCP-NCP stacking. We introduce an NCP-centred set of parameters (NCP-NCP distance, shift, rise, tilt, and others) that allows numerical characterisation of the mutual positions of the NCPs in the stacking and in any other structures formed by the NCP. NCP stacking in more than 140 published NCP crystal structures were analysed. In addition, coarse grained (CG) MD simulations modelling NCP condensation was carried out. The CG model takes into account details of the nucleosome structure and adequately describes the long range electrostatic forces as well as excluded volume effects acting in chromatin. The CG simulations showed good agreement with experimental data and revealed the importance of the H2A and H4 N-terminal tail bridging and screening as well as tail-tail correlations in the stacked nucleosomes.
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| 6. |
- Korolev, Nikolay, et al.
(författare)
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Modelling chromatin structure and dynamics : status and prospects
- 2012
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Ingår i: Current opinion in structural biology. - : Elsevier BV. - 0959-440X .- 1879-033X. ; 22:2, s. 151-159
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Tidskriftsartikel (refereegranskat)abstract
- The packaging of genomic DNA into chromatin in the eukaryotic cell nucleus demands extensive compaction. This requires attractive nucleosome-nucleosome interactions to overcome repulsion between the negatively charged DNA segments as well as other constraints. At the same time, DNA must be dynamically accessible to the cellular machinery that operates on it. Recent progress in the experimental characterisation of the higher order structure and dynamics of well-defined chromatin fibres has stimulated the attempts at theoretical description of chromatin and the nucleosome. Here we review the present status of chromatin Modelling, with particular emphasis on coarse-grained computer simulation models, the role of electrostatic interactions, and discuss future perspectives in the field.
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| 7. |
- Korolev, Nikolay, et al.
(författare)
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Molecular Dynamics Simulations Demonstrate the Regulation of DNA-DNA Attraction by H4 Histone Tail Acetylations and Mutations
- 2014
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Ingår i: Biopolymers. - : Wiley. - 0006-3525 .- 1097-0282. ; 101:10, s. 1051-1064
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Tidskriftsartikel (refereegranskat)abstract
- 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+ mimics the conditions of eukaryotic chromatin. A detailed account of the DNA interactions with the histone tail fragments, K+ 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-counterionDNA structure, interaction and dynamics.
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| 8. |
- Korolev, Nikolay, et al.
(författare)
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Multiscale coarse-grained modelling of chromatin components : DNA and the nucleosome
- 2016
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Ingår i: Advances in Colloid and Interface Science. - : Elsevier BV. - 0001-8686 .- 1873-3727. ; 232, s. 36-48
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Tidskriftsartikel (refereegranskat)abstract
- To model large biomolecular systems, such as cell and organelles an atomistic description is not currently achievable and is not generally practical. Therefore, simplified coarse-grained (CG) modelling becomes a necessity. One of the most important cellular components is chromatin, a large DNA-protein complex where DNA is highly compacted. Recent progress in coarse graining modelling of the major chromatin components, double helical DNA and the nucleosome core particle (NCP) is presented. First, general principles and approaches allowing rigorous bottom-to-top generation of interaction potentials in the CG models are presented. Then, recent CG models of DNA are reviewed and their adequacy is benchmarked against experimental data on the salt dependence of DNA flexibility (persistence length). Furthermore, a few recent CG models of the NCP are described and their application for studying salt-dependent NCP-NCP interaction is discussed. An example of a multiscale approach to CG modelling of chromatin is presented where interactions and self-assembly of thousands of NCPs in solution are observed.
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| 9. |
- Korolev, Nikolay, et al.
(författare)
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The polyelectrolyte properties of chromatin
- 2012
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Ingår i: Soft Matter. - : Royal Society of Chemistry (RSC). - 1744-683X .- 1744-6848. ; 8:36, s. 9322-9333
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Forskningsöversikt (refereegranskat)abstract
- Double helical DNA is a negatively charged polyelectrolyte and exists in the nucleus of living cells as chromatin, a highly compacted but dynamic complex with histone proteins. The first level of DNA compaction is the linear array of the nucleosome core particles (NCP), which is a well-defined structure of 145-147 bp DNA with the histone octamer, connected by linker DNA. Higher levels of chromatin compaction include two routes which may overlap: intramolecular folding of the nucleosome array resulting in formation of the 30 nm fibre and intermolecular aggregation (self-association) between different arrays (or distant fibres of the same chromosome). This review describes how the polyelectrolyte properties of chromatin are illustrated by experimental results of folding and self-association of well-defined model chromatin, in the form of recombinant nucleosome arrays, and how these properties can be understood from computer modelling. Chromatin compaction shows considerable similarities to DNA condensation. However, the structure of condensed chromatin is sensitive to the detailed molecular features of the nucleosome-nucleosome interactions which include the influence of the histone tails and their modifications.
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| 10. |
- Lyubartsev, Alexander P., et al.
(författare)
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Multiscale modelling of nucleosome core particle aggregation
- 2015
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Ingår i: Journal of Physics. - : IOP Publishing. - 0953-8984 .- 1361-648X. ; 27:6
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Tidskriftsartikel (refereegranskat)abstract
- The nucleosome core particle (NCP) is the basic building block of chromatin. Under the influence of multivalent cations, isolated mononucleosomes exhibit a rich phase behaviour forming various columnar phases with characteristic NCP-NCP stacking. NCP stacking is also a regular element of chromatin structure in vivo. Understanding the mechanism of nucleosome stacking and the conditions leading to self-assembly of NCPs is still incomplete. Due to the complexity of the system and the need to describe electrostatics properly by including the explicit mobile ions, novel modelling approaches based on coarse-grained (CG) methods at the multiscale level becomes a necessity. In this work we present a multiscale CG computer simulation approach to modelling interactions and self-assembly of solutions of NCPs induced by the presence of multivalent cations. Starting from continuum simulations including explicit three-valent cobalt(III) hexammine (CoHex(3+)) counterions and 20 NCPs, based on a previously developed advanced CG NCP model with one bead per amino acid and five beads per two DNA base pair unit (Fan et al 2013 PLoS One 8 e54228), we use the inverse Monte Carlo method to calculate effective interaction potentials for a 'super-CG' NCP model consisting of seven beads for each NCP. These interaction potentials are used in large-scale simulations of up to 5000 NCPs, modelling self-assembly induced by CoHex(3+). The systems of 'super-CG' NCPs form a single large cluster of stacked NCPs without long-range order in agreement with experimental data for NCPs precipitated by the three-valent polyamine, spermidine(3+).
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| 11. |
- Minhas, Vishal, et al.
(författare)
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Modeling DNA Flexibility : Comparison of Force Fields from Atomistic to Multiscale Levels
- 2020
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 124:1, s. 38-49
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Tidskriftsartikel (refereegranskat)abstract
- Accurate parametrization of force fields (FFs) is of ultimate importance for computer simulations to be reliable and to possess a predictive power. In this work, we analyzed, in multi-microsecond simulations of a 40-base-pair DNA fragment, the performance of four force fields, namely, the two recent major updates of CHARMM and two from the AMBER family. We focused on a description of double-helix DNA flexibility and dynamics both at atomistic and at mesoscale level in coarse-grained (CG) simulations. In addition to the traditional analysis of different base-pair and base-step parameters, we extended our analysis to investigate the ability of the force field to parametrize a CG DNA model by structure-based bottom-up coarse-graining, computing DNA persistence length as a function of ionic strength. Our simulations unambiguously showed that the CHARMM36 force field is unable to preserve DNA's structural stability at over-microsecond time scale. Both versions of the AMBER FF, parmbsc0 and parmbsc1, showed good agreement with experiment, with some bias of parmbsc0 parameters for intermediate A/B form DNA structures. The CHARMM27 force field provides stable atomistic trajectories and overall (among the considered force fields) the best fit to experimentally determined DNA flexibility parameters both at atomistic and at mesoscale level.
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| 12. |
- Nordenskiöld, Lars, et al.
(författare)
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Liquid-liquid phase separation (LLPS) in DNA and chromatin systems from the perspective of colloid physical chemistry
- 2024
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Ingår i: Advances in Colloid and Interface Science. - 0001-8686. ; 326
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Forskningsöversikt (refereegranskat)abstract
- DNA is a highly charged polyelectrolyte and is prone to associative phase separation driven by the presence of multivalent cations, charged surfactants, proteins, polymers and colloids. The process of DNA phase separation induced by positively charged species is often called DNA condensation. Generally, it refers to either intramolecular DNA compaction (coil-globule transition) or intermolecular DNA aggregation with macroscopic phase separation, but the formation of a DNA liquid crystalline system is also displayed. This has traditionally been described by polyelectrolyte theory and qualitative (Flory-Huggins-based) polymer theory approaches. DNA in the cell nucleus is packed into chromatin wound around the histone octamer (a protein complex comprising two copies each of the four histone proteins H2A, H2B, H3 and H4) to form nucleosomes separated by linker DNA. During the last decade, the phenomenon of the formation of biomolecular condensates (dynamic droplets) by liquid-liquid phase separation (LLPS) has emerged as a generally important mechanism for the formation of membraneless organelles from proteins, nucleic acids and their complexes. DNA and chromatin droplet formation through LLPS has recently received much attention by in vitro as well as in vivo studies that established the importance of this for compartmentalisation in the cell nucleus. Here, we review DNA and chromatin LLPS from a general colloid physical chemistry perspective. We start with a general discussion of colloidal phase separation in aqueous solutions and review the original (pre-LLPS era) work on DNA (macroscopic) phase separation for simpler systems with DNA in the presence of multivalent cations and well-defined surfactants and colloids. Following that, we discuss and illustrate the similarities of such macroscopic phase separation with the general behaviour of LLPS droplet formation by associative phase separation for DNA-protein systems, including chromatin; we also note cases of segregative association. The review ends with a discussion of chromatin LLPS in vivo and its physiological significance.
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| 13. |
- Sun, Tiedong, et al.
(författare)
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A Bottom-Up Coarse-Grained Model for Nucleosome-Nucleosome Interactions with Explicit Ions
- 2022
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 18:6, s. 3948-3960
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Tidskriftsartikel (refereegranskat)abstract
- The nucleosome core particle (NCP) is a large complex of 145–147 base pairs of DNA and eight histone proteins and is the basic building block of chromatin that forms the chromosomes. Here, we develop a coarse-grained (CG) model of the NCP derived through a systematic bottom-up approach based on underlying all-atom MD simulations to compute the necessary CG interactions. The model produces excellent agreement with known structural features of the NCP and gives a realistic description of the nucleosome–nucleosome attraction in the presence of multivalent cations (Mg(H2O)62+ or Co(NH3)63+) for systems comprising 20 NCPs. The results of the simulations reveal structural details of the NCP–NCP interactions unavailable from experimental approaches, and this model opens the prospect for the rigorous modeling of chromatin fibers.
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| 14. |
- Sun, Tiedong, et al.
(författare)
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A multiscale analysis of DNA phase separation : from atomistic to mesoscale level
- 2019
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 47:11, s. 5550-5562
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Tidskriftsartikel (refereegranskat)abstract
- DNA condensation and phase separation is of utmost importance for DNA packing in vivo with important applications in medicine, biotechnology and polymer physics. The presence of hexagonally ordered DNA is observed in virus capsids, sperm heads and in dinoflagellates. Rigorous modelling of this process in all-atom MD simulations is presently difficult to achieve due to size and time scale limitations. We used a hierarchical approach for systematic multiscale coarse-grained (CG) simulations of DNA phase separation induced by the three-valent cobalt(III)-hexammine (CoHex(3+)). Solvent-mediated effective potentials for a CG model of DNA were extracted from all-atom MD simulations. Simulations of several hundred 100-bp-long CG DNA oligonucleotides in the presence of explicit CoHex(3+) ions demonstrated aggregation to a liquid crystalline hexagonally ordered phase. Following further coarse-graining and extraction of effective potentials, we conducted modelling at mesoscale level. In agreement with electron microscopy observations, simulations of an 10.2-kblong DNA molecule showed phase separation to either a toroid or a fibre with distinct hexagonal DNA packing. The mechanism of toroid formation is analysed in detail. The approach used here is based only on the underlying all-atom force field and uses no adjustable parameters and may be generalised to modelling chromatin up to chromosome size.
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| 15. |
- Sun, Tiedong, et al.
(författare)
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All-Atom MD Simulation of DNA Condensation Using Ab lnitio Derived Force Field Parameters of Cobalt(III)-Hexammine
- 2017
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 121:33, s. 7761-7770
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Tidskriftsartikel (refereegranskat)abstract
- It is well established that the presence of the trivalent cobalt(III)-hexammine cation (CoHex(3+)) at submillimolar concentrations leads to bundling (condensation) of double stranded DNA molecules, which is caused by DNA DNA attraction induced by the multivalent counterions. However, the detailed mechanism of this process is still not fully understood. Furthermore, in all-atom molecular dynamics (MD) simulations, spontaneous aggregation of several DNA oligonucleotides in the presence of CoHex(3+) has previously not been, demonstrated. In order to obtain a rigorous description of CoHex(3+)-nucleic acid interactions and CoHex(3+)-induced DNA condensation to be used in MD siniulations, we have derived optimized force field parameters of the CoHex(3+) ion. They were obtained from Car Parrinello molecular dynamics simulation of a single CoHex3+ ion in the presence of 126 water molecules. The new set,of force field parameters reproduces the experimentally known transition of DNA from B- to A-form; and qualitatively describes changes of DNA and RNA persistence lengths. We then carried out a 2 mu s long atomistic simulation of four DNA oligomers each consisting of 36 base pairs in the presence of CoHex(3+). We demonstrate that, in this system, DNA molecules display attractive interactions and aggregate into bundle-like structures. This behavior depends critically on the details of the CoHex(3+) interaction with DNA. A control simulation with a similar setup but in the presence of Mg2+ does not induce DNA DNA attraction, which is also in agreement with experiment.
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| 16. |
- Sun, Tiedong, et al.
(författare)
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Bottom-Up Coarse-Grained Modeling of DNA
- 2021
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Ingår i: Frontiers in Molecular Biosciences. - : Frontiers Media SA. - 2296-889X. ; 8
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Forskningsöversikt (refereegranskat)abstract
- Recent advances in methodology enable effective coarse-grained modeling of deoxyribonucleic acid (DNA) based on underlying atomistic force field simulations. The so-called bottom-up coarse-graining practice separates fast and slow dynamic processes in molecular systems by averaging out fast degrees of freedom represented by the underlying fine-grained model. The resulting effective potential of interaction includes the contribution from fast degrees of freedom effectively in the form of potential of mean force. The pair-wise additive potential is usually adopted to construct the coarse-grained Hamiltonian for its efficiency in a computer simulation. In this review, we present a few well-developed bottom-up coarse-graining methods, discussing their application in modeling DNA properties such as DNA flexibility (persistence length), conformation, melting, and DNA condensation.
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