Towards an experimentally guided global approach in theoretical protein structure prediction

• Applicant: Dr. Alexander Kulesza
• Subject Area: Theoretical Chemistry: Electronic Structure, Dynamics, Simulation ; Biophysics
• Term: from 2014 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 259182989

Protein structure prediction in silico is the holy grail in theoretical biochemistry. It is still not accomplished although high-performance computing is becoming economic and widespread. A bottleneck is the inefficiency of statistical protein structure sampling caused by the vast number of configurations. Thus, not only an increase in the computer power but above all an advancement of theoretical methodology will be necessary in order to make structure prediction possible. It is the goal of this project to develop a global method for this purpose: joining computations with unique structure-sensitive experimental feedback. The main rationale is to reduce the computational time dedicated to sampling those regions of phase space, that are incompatible with the experimental observations and guide the simulation to more important regions. It is a major advantage of gas-phase experiments that they can disentangle intrinsic from external effects on protein conformation. For example, size- and shape-dependent data from Ion-mobility spectrometry (IMS) has been already used to guide adaptively biased molecular dynamics (ABMD) simulations successfully. In this project, a complementary experimental input, based on an Förster Resonant Energy Transfer (FRET) optical gas-phase spectroscopy will be harnessed to bias the simulations. The ABMD approach will be tailored to include a collective biasing coordinate and potential derived from the FRET-related experimental signal. It will be coupled with the existing IMS bias method. The new methods benefit is the sensitive dependence of FRET regarding distance and orientation of single-sites, where the global-shape information of IMS alone is too ambiguous. It will be applied to study alpha-synuclein, a neural tissue protein agglomerating in age-related neuropathological conditions. Theoretical work will be performed among experimentalists who will contribute IMS and action-FRET data from a unique instrument under current development. Overall, this project combines theory and gas phase structural measurements in a unifying way, thus offering a new approach in the global strategy for structural biology and in particular for research on proteopathic diseases.

• DFG Programme: Research Fellowships
• International Connection: France
• Host: Dr. Philippe Dugourd