Computational Advances in Structural Biology

Abstract:

Small-angle X-ray scattering (SAXS) is a powerful method in the studies of solutions of biological macromolecules and nanostructured systems [1] allowing one to analyze the structure of native particles and complexes and to rapidly assess structural changes in response to variations in external conditions. Dedicated high brilliance synchrotron beamlines, novel data analysis methods [2] and new on-line purification approaches [3] significantly enhanced resolution and reliability of the structural models provided by SAXS. Very important is the ability of SAXS to quantitatively characterize complicated systems and mixtures in native environments and to see the biomolecules in action by rapidly observing responses to changing physical and chemical conditions (e.g. upon pH or temperature changes, ligand binding etc).

Given the limited information content in the scattering data, robust data analysis and modelling methods are of major importance for broad applications of solution SAXS in biology. To reduce the ambiguity of interpretation, SAXS is often utilized together with other structural methods like crystallography, NMR and electron microscopy (EM). In classical applications, SAXS generally yields low resolution quaternary structures but, very importantly, the method can also help to analyze equilibrium mixtures and to visualize flexible portions, not seen by the high resolution methods. SAXS is readily combined with computational, biophysical and biochemical techniques and it is straightforward to utilize the high resolution models from cryo-EM and AlpfaFold2 in the hybrid modelling procedures.

In the present talk, modern methods for SAXS data analysis will be presented and illustrated by applications to characterize structures and conformational transitions of macromolecules in solution. Specifically, a number of recent SAXS applications to Covid-19 related targets will be given. These include high-throughput studies of antibodies for the receptor binding domain of SARS-CoV-2 spike protein, oligomeric states analysis of the Covid non-structural protein complexes and characterization of lipid nanoparticles employed for the mRNA vaccines.