The goal of the project is a deeper understanding of DNA compaction and thus gene expression and gene transcription based on an all atom model. In the nucleosome core particle, the basic unit of chromatin, DNA is wrapped around a protein core, build by an octamer of histone proteins H3, H4, H2A and H2B (see figure). For access to genomic DNA by proteins involved in the control and expression of the genome the nucleosome has to undergo structural remodeling including unwrapping of nucleosomal DNA segments from the nucleosome core. The positively charged tails of the histones seem to play an important role in this process. A former study showed that a truncation of the tails, similar to post-transcriptional modifications, such as acetylation, methylation or phosphorylation, results in a destabilization of the histone core, probably due to the absence of histone-histone and histone-DNA polar contacts (Ref. 1). The latter are known to influence nucleosome dynamics and gene transcription. A further project studying DNA unwrapping using coarse grained simulations showed a long-lived DNA detachment from the nucleosome. Part of the long-lived DNA detachment is a binding of the H3 tail to the protein core blocking the DNA from rebinding to that. A removal of the H3 tails causes the long-lived detachments to disappear. The results suggest that the H3 tail may stabilize the nucleosome in the open state during the initial stages of the nucleosome remodeling process (Ref. 2).
The questions we aim to answer are:
In addition to single MD simulations we are using replica exchange molecular dynamics (REMD) simulations to accelerate the generation of conformations and to overcome high energy barriers in the conformational space. The REMD method involves simulating multiple replicas of the system at different temperatures and randomly exchanging the complete state of two replicas which is comparable to a heating and cooling of the system.
The goal of a further study is to understand the effect of post-transcriptional modifications, such as acetylation or methylation on the nucleosome and tail dynamics.
Results will be compared to results of spFRET measurements (see experimental part) where the DNA surface and histone tails are labeled to study the distance and thus a possible binding of the histone tails to the DNA surface.