A Benchmark Study of Protein-Fragment Complex Structure Calculations with NMR2
- Author(s)
- Felix Torres, Gabriela Stadler, Witek Kwiatkowski, Julien Orts
- Abstract
Protein–fragment complex structures are particularly sought after in medicinal chemistry to rationally design lead molecules. These structures are usually derived using X-ray crystallography, but the failure rate is non-neglectable. NMR is a possible alternative for the calculation of weakly interacting complexes. Nevertheless, the time-consuming protein signal assignment step remains a barrier to its routine application. NMR Molecular Replacement (NMR
2) is a versatile and rapid method that enables the elucidation of a protein–ligand complex structure. It has been successfully applied to peptides, drug-like molecules, and more recently to fragments. Due to the small size of the fragments, ca < 300 Da, solving the structures of the protein–fragment complexes is particularly challenging. Here, we present the expected performances of NMR
2 when applied to protein–fragment complexes. The NMR
2 approach has been benchmarked with the SERAPhic fragment library to identify the technical challenges in protein–fragment NMR structure calculation. A straightforward strategy is proposed to increase the method’s success rate further. The presented work confirms that NMR
2 is an alternative method to X-ray crystallography for solving protein–fragment complex structures.
- Organisation(s)
- Department of Pharmaceutical Sciences
- External organisation(s)
- Eidgenössische Technische Hochschule Zürich
- Journal
- International Journal of Molecular Sciences
- Volume
- 24
- ISSN
- 1422-0067
- DOI
- https://doi.org/10.3390/ijms241814329
- Publication date
- 09-2023
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 104026 Spectroscopy, 106006 Biophysics
- Keywords
- ASJC Scopus subject areas
- Catalysis, Molecular Biology, Spectroscopy, Computer Science Applications, Physical and Theoretical Chemistry, Organic Chemistry, Inorganic Chemistry
- Portal url
- https://ucris.univie.ac.at/portal/en/publications/a-benchmark-study-of-proteinfragment-complex-structure-calculations-with-nmr2(7d2184a6-92da-4987-b3c1-84fbb2b67d3c).html