The Centre for Computational Science


Anton Awards at National Resource for Biomedical Supercomputing

Understanding the Role of Dynamics in Human Histone Deacetylase 8 Substrate Binding and Release


Units: 100,000 Anton node hours
Effective Dates: 2012-2013

Building on the results of our previous allocation we aim to elucidate how the human histone deacetylase 8 (HDAC8) binds its substrate, and in particular what role the dynamics of this flexible enzyme play in this mechanism. HDAC enzymes play a crucial role in post-translational modification of histones and are promising targets for cancer treatment, with two HDAC inhibitors recently approved by the food and drug administration of the United States. So far, experimental studies have shown that this protein contains specific flexible regions and it has been suggested that the malleability of the enzyme is linked to its activity. In our previous work including an Anton allocation we identified energetically low lying states interconverting on the microsecond timescale that we can associate with binding or release of substrate [cite our submitted paper] (see progress report). On the basis of these simulations we are able to propose how a single point mutation, which mimics phosphorylation of this site and is known to down regulate the enzyme, changes the sampling of the aforementioned states. Understanding of such mechanisms and states is expected to lead the way for novel drug design strategies. Using Anton we expect to be the first to observe a substrate:HDAC8 binding process wherein the protein samples binding and non-binding states, thereby shining light more generally on the role of dynamics in the binding processes of flexible enzymes on a microscopic scale.