2021 Fiscal Year Research-status Report
Characterizing the mechanism of chromatin remodeling by molecular dynamics simulations
| Project/Area Number |
20K06587
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | nucleosome / molecular dynamics / chromatin remodeling |
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| Outline of Annual Research Achievements |
Over the past year, we run extensive (microsecond-long) all-atom molecular dynamics simulations of histones in complex with DNA. By comparing the effect of DNA sequence and base-pair mismatches, our simulations highlighted very interesting changes in nucleosomal DNA structure and dynamics, which show how such features may impact the activity of chromatin remodelers, as found in past experimental observations. Furthermore, coarse-grained molecular dynamics simulations of full nucleosomes allowed us to explore longer time scales for a wide variety of DNA sequences, and further complement the insights obtained from the all-atom simulations.
These unbiased simulations turned out to be unsuitable for Markov state modeling due to the slow timescales of the process investigated. However, we now optimized a series of collective variables that should allow us to reconstruct the free energy landscape of nucleosome sliding using the string method implemented in the software Genesis, as originally planned. Preliminary results in this direction were presented at the last Annual Meeting of the Biophysical Society of Japan in 2021.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
We expanded the scope of the project by exploring the effect of DNA sequence and base-pair mismatches on nucleosome sliding, for which long unbiased all-atom simulations already provided very interesting insights into chromatin remodeling. The reconstruction of the free energy landscape of nucleosome sliding is ongoing and we should be able to complete our calculations soon.
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| Strategy for Future Research Activity |
This year we will complete our analysis of our long unbiased molecular to characterize in detail how DNA sequence and mismatches affect nucleosomal DNA structure and sliding. We will also try to compare our results with the available experiments on chromatin remodeling to provide a clear understanding of how the features of DNA can affect this important biological process. Finally, we will run string method calculations to reconstruct the free energy landscape of nucleosome sliding to further clarify this mechanism down to the molecular level. The results will be presented at a major international conference in Japan and we hope we will be able to publish some of our findings in the very near future.
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| Causes of Carryover |
The incurring amount will be mainly used to buy computational resources from the Kyoto University supercomputer center and expand the local cpu cluster in our laboratory. Also, we will present our results at at least one conference within Japan or abroad. Using these supercomputer resources, we will run unbiased and string method molecular dynamics simulations to characterize the nucleosome repositioning process.
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