Mechanism for verification of mismatched and homoduplex DNAs by nucleotides-bound MutS analyzed by molecular dynamics simulations

Ishida, Hisashi; Matsumoto, Atsushi

doi:10.1002/prot.25077

Cited by 11 publications

(9 citation statements)

References 67 publications

(167 reference statements)

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“…To evaluate the free energy for unwrapping nucleosomal DNA from the histone core, the adaptively biased molecular dynamics (ABMD) method [ 52 ] combined with the multiple walker method [ 53 ] was implemented using an in-house software program, SCUBA [ 54 – 58 ]. To minimize the computational cost, we separated the outer DNA unwrapping process into two stages.…”

Section: Methodsmentioning

confidence: 99%

Free energy profiles for unwrapping the outer superhelical turn of nucleosomal DNA

2018

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The eukaryotic genome is packaged into a nucleus in the form of chromatin. The fundamental structural unit of chromatin is a protein-DNA complex, the nucleosome, where 146 or 147 base pairs of DNA wrap 1.75 times around a histone core. To function in cellular processes, however, nucleosomal DNA must be unwrapped. Although this unwrapping has been experimentally investigated, details of the process at an atomic level are not yet well understood. Here, we used molecular dynamics simulation with an enhanced sampling method to calculate the free energy profiles for unwrapping the outer superhelical turn of nucleosomal DNA. A free energy change of about 11.5 kcal/mol for the unwrapping agrees well with values obtained in single molecule experiments. This simulation revealed a variety of conformational states, indicating there are many potential paths to outer superhelicdal turn unwrapping, but the dominant path is likely asymmetric. At one end of the DNA, the first five bps unwrap, after which a second five bps unwrap at the same end with no increase in free energy. The unwrapping then starts at the other end of the DNA, where 10 bps are unwrapped. During further unwrapping of 15 bps, the unwrapping advances at one of the ends, after which the other end of the DNA unwraps to complete the unwrapping of the outer superhelical turn. These results provide insight into the construction, disruption, and repositioning of nucleosomes, which are continuously ongoing during cellular processes.

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Section: Methodsmentioning

confidence: 99%

Free energy profiles for unwrapping the outer superhelical turn of nucleosomal DNA

2018

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“…MD Simulations of the Systems in Water. Simulations were carried out using an MD simulation program called SCUBA (20,(47)(48)(49)(50)(51)(52) with the AMBER ff14SB (53), bsc1 (54), and ff99ions08 (55) force-fields for the octamer, DNAs, and ions, respectively. The structure of nucleosome was placed in a rectangular box of ∼125 Å × 245 Å × 155 Å (SI Appendix, Fig.…”

Section: Methodsmentioning

confidence: 99%

Torsional stress can regulate the unwrapping of two outer half superhelical turns of nucleosomal DNA

Ishida

Kono

2021

Proc. Natl. Acad. Sci. U.S.A.

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Torsional stress has a significant impact on the structure and stability of the nucleosome. RNA polymerase imposes torsional stress on the DNA in chromatin and unwraps the DNA from the nucleosome to access the genetic information encoded in the DNA. To understand how the torsional stress affects the stability of the nucleosome, we examined the unwrapping of two half superhelical turns of nucleosomal DNA from either end of the DNA under torsional stress with all-atom molecular dynamics simulations. The free energies for unwrapping the DNA indicate that positive stress that overtwists DNA facilitates a large-scale asymmetric unwrapping of the DNA without a large extension of the DNA. During the unwrapping, one end of the DNA was dissociated from H3 and H2A-H2B, while the other end of the DNA stably remained wrapped. The detailed analysis indicates that this asymmetric dissociation is facilitated by the geometry and bendability of the DNA under positive stress. The geometry stabilized the interaction between the major groove of the twisted DNA and the H3 αN-helix, and the straightened DNA destabilized the interaction with H2A-H2B. Under negative stress, the DNA became more bendable and flexible, which facilitated the binding of the unwrapped DNA to the octamer in a stable state. Consequently, we conclude that the torsional stress has a significant impact on the affinity of the DNA and the octamer through the inherent nature of the DNA and can change the accessibility of regulatory proteins.

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“…(ABMD) method [22] combined with multiple walker method [23] implemented in an in-house molecular dynamics simulation software, SCUBA [16,[24][25][26][27][28] which was initiated to develop by Prof. Go and was named after his hobby. The reaction coordinate d was defined as a distance between two phosphorus atoms of T73 in chains I and J at both DNA ends.…”

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Free energy profile for unwrapping outer superhelical turn of CENP-A nucleosome

2019

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Eukaryotic genome is packaged in a nucleus in the form of chromatin. The fundamental structural unit of the chromatin is the protein-DNA complex, nucleosome, where DNA of about 150 bp is wrapped around a histone core almost twice. In cellular processes such as gene expression, DNA repair and duplication, the nucleosomal DNA has to be unwrapped. Histone proteins have their variants, indicating there are a variety of constitutions of nucleosomes. These different constitutions are observed in different cellular processes. To investigate differences among nucleosomes, we calculated free energy profiles for unwrapping the outer superhelical turn of CENP-A nucleosome and compared them with those of the canonical nucleosome. The free energy profiles for CENP-A nucleosome suggest that CENP-A nucleo some is the most stable when 16 to 22 bps are unwrapped in total whereas the canonical nucleosome is the most stable when it is fully wrapped. This indicates that the flexible conformation of CENP-A nucleosome is ready to provide binding sites for the structural integrity of the centromere.

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Mechanism for verification of mismatched and homoduplex DNAs by nucleotides-bound MutS analyzed by molecular dynamics simulations

Cited by 11 publications

References 67 publications

Free energy profiles for unwrapping the outer superhelical turn of nucleosomal DNA

Free energy profiles for unwrapping the outer superhelical turn of nucleosomal DNA

Torsional stress can regulate the unwrapping of two outer half superhelical turns of nucleosomal DNA

Free energy profile for unwrapping outer superhelical turn of CENP-A nucleosome

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