Rapid interpretation of small-angle X-ray scattering data

The fundamental aim of structural analyses in biophysics is to reveal a mutual relation between a molecule’s dynamic structure and its physiological function. Small-angle X-ray scattering (SAXS) is an experimental technique for structural characterization of macromolecules in solution and enables time-resolved analysis of conformational changes under physiological conditions. As such experiments measure spatially averaged low-resolution scattering intensities only, the sparse information obtained is not sufficient to uniquely reconstruct a three-dimensional atomistic model. Here, we integrate the information from SAXS into molecular dynamics simulations using computationally efficient native structure-based models. Dynamically fitting an initial structure towards a scattering intensity, such simulations produce atomistic models in agreement with the target data. In this way, SAXS data can be rapidly interpreted while retaining physico-chemical knowledge and sampling power of the underlying force field. We demonstrate our method’s performance using the example of three protein systems. Simulations are faster than full molecular dynamics approaches by more than two orders of magnitude and consistently achieve comparable accuracy. Computational demands are reduced sufficiently to run the simulations on commodity desktop computers instead of high-performance computing systems. These results underline that scattering-guided structure-based simulations provide a suitable framework for rapid early-stage refinement of structures towards SAXS data with particular focus on minimal computational resources and time.Author summary: Proteins are the molecular nanomachines in biological cells and thus vital to any known form of life. From the evolutionary perspective, viable protein structure emerges on the basis of a ‘form-follows-function’ principle. A protein’s designated function is inextricably linked to dynamic conformational changes, which can be observed by small-angle X-ray scattering. Intensities from SAXS contain low-resolution information on the protein’s shape at different steps of its functional cycle. We are interested in directly getting an atomistic model of this encoded structure. One powerful approach is to include the experimental data into computational simulations of the protein’s function-related physical motions. We combine scattering intensities with coarse-grained native structure-based models. These models are computationally highly efficient yet describe the system’s dynamics realistically. Here, we present our method for rapid interpretation of scattering intensities from SAXS to derive structural models, using minimal computational resources and time.