*BBSRC EASTBIO Programme* Structural Characterisation of Chromatin Remodelling Enzymes

The genomes of eukaryotes exist as chromatin. The way that chromatin is organised is used as a means of regulating access to the underlying genetic information. Altering the conformation is achieved through the co-ordinated action of a series of different types of alteration to chromatin. These include, DNA methylation, post-translational modification of histones and association with a variety of nucleosome binding proteins. In addition the action of an extended family of motor proteins can act to reconfigure the structure of chromatin (Narlikar et al., 2013). Typically, these enzymes consist of a catalytic subunit with a number of accessory subunits. Recently, it has been found that mutations to different subunits of the human SWI/SNF chromatin remodelling complex occur at surprisingly high frequencies across a broad range of cancers with potential therapeutic value (Hohmann and Vakoc, 2014).

In order to understand how these enzymes function it is important that the structure of enzymes and their mode of interaction with nucleosomes is determined. Cryo Elelctron microscopy has recently been shown to be suited as a means of studying nucleosome-enzyme complexes. In this proposal similar approaches will be applied to study the structural organisation of different chromatin remodelling ATPases. The structures obtained will represent snapshots in the ATP-dependent reaction cycle of these enzymes. We will use all atom molecular dynamics to model how conformational changes occur during the reaction cycle. The molecular dynamics approaches will be similar to those used to study conformational changes in ion channels (Kutzner et al., 2016). In combination, these will provide new understanding into how that action of these complexes is subverted in cancer.

***Application details and more information on the BBSRC EASTBIO Doctoral Training Partnership can be found at the website below. You must follow the instructions for your application to be considered:

http://www.eastscotbiodtp.ac.uk/how-apply-0