High-Resolution Structure Determination of Protein-Ligand Complexes with Solution Scattering
Thomas D. Grant, Sarah R. Chamberlain, Jitendra Singh, Patrick Kwabena Oduro · Structural Dynamics · 2025
Protein-ligand interactions play a pivotal role in drug discovery and understanding biological processes. Structural biology techniques, such as X-ray crystallography, offer atomic-level insights into these interactions in a static environment. X-ray solution scattering (XSS) is a valuable tool for studying proteins in solution due to its ability to provide low-resolution structural information complementary to high-resolution techniques, and it can be performed in high throughput at modern X-ray sources. In this presentation, we describe our algorithm called DENSS, which reconstructs ab initio density maps directly from XSS data. DENSS is unique in its ability to probe many types of systems including soluble and membrane proteins, lipid nanoparticles, RNA/DNA, and even non-biological systems and non-aqueous solutions, and is compatible with both X-ray and neutron scattering. We discuss our latest developments in DENSS, which couple XSS with known structural information to enable us to probe the structure of protein-ligand complexes in solution at high resolution. Our developments, coupled with the ability to perform XSS at room temperature and in high throughput, represent a significant advancement in the field of structural biology and drug discovery.