Micha Kunze, Flemming Hansen and Peter Coveney have published an article in the Journal of the American Chemical Society on the enzymatic activity of the human histone deacetylase 8. You can find the paper here.
We applied cutting-edge molecular dynamics simulations to investigate how the molecular dynamics influences the activity of the human histone deacetylase 8 (HDAC8); a key player in gene-regulation and cancer treatment target. Using long-time scale molecular dynamics simulations, carried out with GROMACS 4.5.3 on the UCL Legion cluster and with specialised hardware on the ANTON supercomputer, we found that two loops (L1 and L2) dynamically interact, which in turn allsoterically alters the conformation of functionally important residues.
Based on this observation we designed and produced mutants of the HDAC8 enzyme to investigate experimentally what role the dynamic loop interactions play on in vitro enzymatic activity. In the Hansen Lab we tested these mutations with a fluorogenic and a novel p53-tail progression assay we developed, which uses nuclear magnetic resonance (NMR) spectroscopy to follow the deacetylation reaction quantitatively. The experimental results clearly support our theoretical prediction that the dynamics loop interactions play a vital role in the catalytic cycle of HDAC8.
The success of this project exemplifies the potential of molecular simulations to guide biophysical investigations, and vice versa, in an interdisciplinary manner.