Structure and ensemble refinement against SAXS data: combining MD simulations with Bayesian inference or with the maximum entropy principle

Abstract

Small-angle X-ray scattering (SAXS) is a powerful method for tracking conformational transitions of proteins or soft-matter complexes in solution. However, the interpretation of the experimental data is challenged by the low spatial resolution and the low information content of the data, which lead to a high risk of overinterpreting the data. Here, we illustrate how SAXS data can be integrated into all-atom molecular dynamics (MD) simulation to derive atomic structures or heterogeneous ensembles that are compatible with the data. Besides providing atomistic insight, the MD simulation adds physico-chemical information, as encoded in the MD force fields, which greatly reduces the risk of overinterpretation. We present an introduction into the theory of SAXS-driven MD simulations as implemented in GROMACS-SWAXS, a modified version of the GROMACS simulation software. We discuss SAXS-driven parallel-replica ensemble refinement with commitment to the maximum entropy principle as well as a Bayesian formulation of SAXS-driven structure refinement. Practical considerations for running and interpreting the simulations are presented. The methods are freely available via GitLab at https://gitlab.com/cbjh/gromacs-swaxs.