A Benchmark Study of Protein–Fragment Complex Structure Calculations with NMR2

• Published in: International journal of molecular sciences Vol. 24; no. 18; p. 14329
• Main Authors: Torres, Felix, Stadler, Gabriela, Kwiatkowski, Witek, Orts, Julien
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 20.09.2023; MDPI
• Subjects: Algorithms; Binding sites; complex structure; Crystallography; Datasets; Design optimization; drug design; FBDD; fragment; Global positioning systems; GPS; Ligands; Market entry; NMR spectroscopy; NMR2; Proteins; Success
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241814329

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 (NMR2) 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 NMR2 when applied to protein–fragment complexes. The NMR2 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 NMR2 is an alternative method to X-ray crystallography for solving protein–fragment complex structures.