‘Computational tools for bridging the resolution gap in structural biology’

Federico Morán Abad, Jose Manuel Andreu Morales, José María Valpuesta Moralejo, Pablo Chacón Montes.

Determination of the low and mid resolution structures of proteins, macromolecular complexes and assemblies is central in identifying their functional mechanisms.

The most powerful experimental approaches that yield this information include microscopy (cryo-electron, atomic force, tomography), complemented by hydrodynamic analysis, spectroscopy methods such as fluorescence resonance energy transfer (FRET), and neutron and X-ray solution scattering (SAXS). Despite their limited resolution (1-4nm), these techniques enable us to obtain valuable structural information in a wide range of near physiological conditions, or even perform time-resolved experiments. The possibility to extend the resolution of these experimental data to near-atomic level by combination with other structural information sources (e.g. X-ray data) could give us the key to understanding at high resolution the function and dynamics of the macromolecular systems that govern the cellular process. In addition, most of these techniques have currently entered the structural genomic era, i.e. there are several projects to obtain high throughput of structural experimental data from EM and SAXS. These initiatives, together with the exponential growth of structures at atomic resolution coming from X-ray crystallography and NMR, call for bioinformatic tools that enable the combination of structural information at different resolutions.

The main objective of this proposal is to develop the bridging technology for merging such multi-resolution structural information. On the one hand, by docking atomic structures into EM density maps and advancing the development of computational tools for shape and size ab initio determinations from SAXS solution scattering. On the other hand, by introducing conformational flexibility using Normal Mode Analysis.