Experiences From Developing Software for Large X-Ray Crystallography-Driven Protein-Ligand Studies

The throughput of macromolecular X-ray crystallography experiments has surged over the last decade. This remarkable gain in efficiency has been facilitated by increases in the availability of high-intensity X-ray beams, (ultra)fast detectors and high degrees of automation. These developments have in turn spurred the development of several dedicated centers for crystal-based fragment screening which enable the preparation and collection of hundreds of single-crystal diffraction datasets per day. Crystal structures of target proteins in complex with small-molecule ligands are of immense importance for structure-based drug design (SBDD) and their rapid turnover is a prerequisite for accelerated development cycles. While the experimental part of the process is well defined and has by now been established at several synchrotron sites, it is noticeable that software and algorithmic aspects have received far less attention, as well as the implications of new methodologies on established paradigms for structure determination, analysis, and visualization. We will review three key areas of development of large-scale protein-ligand studies. First, we will look into new software developments for batch data processing, followed by a discussion of the methodological changes in the analysis, modeling, refinement and deposition of structures for SBDD, and the changes in mindset that these new methods require, both on the side of depositors and users of macromolecular models. Finally, we will highlight key new developments for the presentation and analysis of the collections of structures that these experiments produce, and provide an outlook for future developments.

Automated summary

The throughput of macromolecular X-ray crystallography experiments has significantly increased over the last decade due to advancements in X-ray beams, detectors, and automation. This has led to the establishment of dedicated centers for crystal-based fragment screening and the ability to collect hundreds of single-crystal diffraction datasets per day. Crystal structures of proteins with small-molecule ligands are crucial for structure-based drug design, but there has been less focus on software and algorithmic aspects and the impact of new methodologies on established paradigms.