Experiences From Developing Software for Large X-Ray Crystallography-Driven Protein-Ligand Studies
(2022) In Frontiers in Molecular Biosciences 9.- Abstract
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... (More)
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.
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- author
- Pearce, Nicholas M. ; Skyner, Rachael and Krojer, Tobias LU
- organization
- publishing date
- 2022
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- data management, data presentation and analysis, fragment screening, macromolecular crystallography, multi-state modelling
- in
- Frontiers in Molecular Biosciences
- volume
- 9
- article number
- 861491
- publisher
- Frontiers Media S. A.
- external identifiers
-
- scopus:85128897151
- pmid:35480897
- ISSN
- 2296-889X
- DOI
- 10.3389/fmolb.2022.861491
- language
- English
- LU publication?
- yes
- id
- f1d5640f-d90f-4136-87ad-97c78d6a3b45
- date added to LUP
- 2022-06-29 14:28:03
- date last changed
- 2024-09-19 20:31:17
@article{f1d5640f-d90f-4136-87ad-97c78d6a3b45, abstract = {{<p>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.</p>}}, author = {{Pearce, Nicholas M. and Skyner, Rachael and Krojer, Tobias}}, issn = {{2296-889X}}, keywords = {{data management; data presentation and analysis; fragment screening; macromolecular crystallography; multi-state modelling}}, language = {{eng}}, publisher = {{Frontiers Media S. A.}}, series = {{Frontiers in Molecular Biosciences}}, title = {{Experiences From Developing Software for Large X-Ray Crystallography-Driven Protein-Ligand Studies}}, url = {{http://dx.doi.org/10.3389/fmolb.2022.861491}}, doi = {{10.3389/fmolb.2022.861491}}, volume = {{9}}, year = {{2022}}, }