Getting more from low-resolution methods: the combination of SAXS and atomistic molecular simulation

A protein's biological function is not only determined by the spatial arrangement of atoms but also by the dynamics of its conformational landscape. Molecular structure determination from high-resolution methods (X-ray crystallography and cryoEM) reveal atomistic details but often hide the dynamics critical to function. Small angle X-ray scattering (SAXS), on the other hand, provides structural information in the solution state, but is limited in terms of resolution. In this proposal, methods and tools will be developed to combine atomistic molecular simulations with SAXS data, to extend the structural information from SAXS experiments to higher resolution. Ab initio modelling of protein structure using SAXS is unable to deliver structures with the atomistic-level resolution required to fully understand biological function. This proposal solves this problem.
A significant problem affecting routine MD simulation with SAXS relates to the technical difficulties running the calculations. Each step requires experience in the relevant software. However, automation is possible. Our Protocaller software automates the workflow for protein MD simulations for calculating ligand binding free energies. This software has been incorporated into the Galaxy bioinformatics platform, improving the accessibility, shareability, and reproducibility of computational methods for molecular simulations. Here, we will extend this software to automate the application of advanced MD simulations to the structural analysis of SAXS data.