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.

Unraveling the Structure – Dynamics – Function Relationship of Human Histone Deacetylase 8

Units: 50,000 Anton node hours
Effective Dates: 04-Oct-2011 to 31-May-2012

In this work, we plan to investigate histone deacetylase 8 (HDAC8), which regulates the acetylation state of histones. HDAC inhibitors have been approved for lymphoma, but are not very specific toward the 18 different isoforms in humans. The aim of the proposed work is to combine MD, NMR, drug design and synthesis to develop improved inhibitors that can trap intermediates and inactivate HDACs. Lipari-Szabo order parameters and CPMG relaxation-dispersion will be computed from molecular dynamics trajectory data and compared with NMR experiments.

The work will form part of the PhD research of Micha Kunze, who is on a Wellcome Trust funded PhD studentship at UCL. Micha spent three months this summer working on a closely related project as one of his three required first year course rotations. Micha starts his PhD work with us in early October 2011. He will be co-supervised by Dr Flemming Hansen at the UCL Department of Structural and Molecular Biology.

Characterizing changes in the conformation and dynamics of epidermal growth factor receptor induced by mutations associated with anti-cancer drug treatment

Units: 50,000 Anton node hours
Effective Dates: 01-Apr-2011 for 5-6 months

Professor P Coveney, as a Yale faculty adjunct, has been awarded 50,000 node hours on Anton, a massively parallel special purpose supercomputer designed and built by D. E. Shaw Research for exceptionally fast protein folding simulation. The project is titled “Characterizing changes in the conformation and dynamics of epidermal growth factor receptor induced by mutations associated with anti-cancer drug treatment”. The effective date is 01-Apr-2011 and the project will last for 5-6 months.