Magnetic resonance in biology: A new paradigm for local and global structural analysis of nano-machines (360G-Wellcome-093471_Z_10_Z)

Taken together the overall objective is to characterise the energy landscape and reaction coordinate of HDAC8, especially of the active site, by combining experimental and computational work. The combination of all atom simulations and experimental data will allow us to accurately dissect static and dynamic contributions to the catalytic activity of the enzyme, which is a controversial topic in cutting edge enzyme research [Adamczyk et al. 2011 and Bhabha et al. 2011]. A further aspect is the work on HDAC inhibitors and their interaction with the protein. Detection of the binding mode and elucidations of the inhibitory mechanisms can be achieved by employing the above methods, since the currently available inhibitors mainly interfere with the catalytic site. Work on these inhibitors is done in collaboration with Prof. Charles Marson (UCL Chemistry). Furthermore, our research could provide novel ways to inhibit HDACs. On a methodological level the project could include the development of simple, yet accurate, descriptions of the nuclear-electron interactions that will allow for determining the dynamics and local structural fluctuations of paramagnetic metal sites of proteins. The methodology to be developed during the project will be applicable to elucidate the local structure and dynamics of paramagnetic sites of proteins in general. All parts of the project are clearly interdisciplinary in nature since the main objective is to obtain novel information about bio-nano-machines by combining EPR, NMR and simulations, thus bringing together physical, biological, chemical and computational sciences.