Dataset Information

A Bottom-Up Coarse-Grained Model for Nucleosome-Nucleosome Interactions with Explicit Ions.

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.

SUBMITTER: Sun T

PROVIDER: S-EPMC9202350 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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A Bottom-Up Coarse-Grained Model for Nucleosome-Nucleosome Interactions with Explicit Ions.

Sun Tiedong T Minhas Vishal V Mirzoev Alexander A Korolev Nikolay N Lyubartsev Alexander P AP Nordenskiöld Lars L

Journal of chemical theory and computation 20220517 6

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 nucle ...[more]

PMID: 35580041

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Project description:Reversible protein cluster formation is an important initial step in the processes of native and non-native protein aggregation, but involves relatively long time and length scales for detailed atomistic simulations and extensive mapping of free energy landscapes. A coarse-grained (CG) model is presented to semiquantitatively characterize the thermodynamics and key configurations involved in the landscape for protein oligomerization, as well as experimental measures of interactions such as the osmotic second virial coefficient (B22). Based on earlier work (Grüenberger et al., J. Phys. Chem. B 2013, 117, 763), this CG model treats proteins as rigid bodies composed of one bead per amino acid, with each amino acid having specific parameters for its size, hydrophobicity, and charge. The net interactions are a combination of steric repulsions, short-range attractions, and screened long-range charge-charge interactions. Model parametrization was done by fitting simulation results against experimental value of B22 as a function of solution ionic strength for ?-chymotrypsinogen A and ?D-Crystallin (gD-Crys). The CG model is applied to characterize the pairwise interactions and dimerization of gD-Crys and the dependence on temperature, protein concentration, and ionic strength. The results illustrate that at experimentally relevant conditions where stable dimers do not form, the entropic contributions are predominant in the free-energy of protein cluster formation and colloidal protein interactions, arguing against interpretations that treat B22 primarily from energetic considerations alone. Additionally, the results suggest that electrostatic interactions help to modulate the population of the different stable configurations for protein nearest-neighbor pairs, while short-range attractions determine the relative orientations of proteins within these configurations. Finally, simulation results are combined with Principal Component Analysis to identify those amino-acids/surface patches that form interprotein contacts at conditions that favor dimerization of gD-Crys. The resulting regions agree with previously found aggregation-prone sites, as well as suggesting new ones that may be important.

Dataset Information

A Bottom-Up Coarse-Grained Model for Nucleosome-Nucleosome Interactions with Explicit Ions.

Publications

A Bottom-Up Coarse-Grained Model for Nucleosome-Nucleosome Interactions with Explicit Ions.

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