Getting the chemistry right: protonation, tautomers and the importance of H atoms in biological chemistry
| العنوان: | Getting the chemistry right: protonation, tautomers and the importance of H atoms in biological chemistry |
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| المؤلفون: | Chun-wa Chung, Benjamin D. Bax, Colin M. Edge |
| المصدر: | Acta Crystallographica. Section D, Structural Biology |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Models, Molecular, Saccharomyces cerevisiae Proteins, Double bond, Proton, Protein Conformation, Protonation, Crystal structure, Saccharomyces cerevisiae, 010402 general chemistry, Crystallography, X-Ray, chemistry, 01 natural sciences, Catalysis, Small Molecule Libraries, 03 medical and health sciences, tautomers, Isomerism, Structural Biology, Computational chemistry, Atom, chemistry.chemical_classification, Chemistry, Ligand, ligands, Proteins, DNA, Tautomer, Research Papers, 0104 chemical sciences, 030104 developmental biology, DNA Topoisomerases, Type II, H atoms, Protons, Crystallization, Hydrogen |
| الوصف: | H atoms are ‘hard to see’ in X-ray crystal structures of protein–ligand complexes. This paper discusses the problem of identifying the correct tautomeric form(s) of protein-bound ligands. There are more H atoms than any other type of atom in an X-ray crystal structure of a protein–ligand complex, but as H atoms only have one electron they diffract X-rays weakly and are ‘hard to see’. The positions of many H atoms can be inferred by our chemical knowledge, and such H atoms can be added with confidence in ‘riding positions’. For some chemical groups, however, there is more ambiguity over the possible hydrogen placements, for example hydroxyls and groups that can exist in multiple protonation states or tautomeric forms. This ambiguity is far from rare, since about 25% of drugs have more than one tautomeric form. This paper focuses on the most common, ‘prototropic’, tautomers, which are isomers that readily interconvert by the exchange of an H atom accompanied by the switch of a single and an adjacent double bond. Hydrogen-exchange rates and different protonation states of compounds (e.g. buffers) are also briefly discussed. The difference in heavy (non-H) atom positions between two tautomers can be small, and careful refinement of all possible tautomers may single out the likely bound ligand tautomer. Experimental methods to determine H-atom positions, such as neutron crystallography, are often technically challenging. Therefore, chemical knowledge and computational approaches are frequently used in conjugation with experimental data to deduce the bound tautomer state. Proton movement is a key feature of many enzymatic reactions, so understanding the orchestration of hydrogen/proton motion is of critical importance to biological chemistry. For example, structural studies have suggested that, just as a chemist may use heat, some enzymes use directional movement to protonate specific O atoms on phosphates to catalyse phosphotransferase reactions. To inhibit ‘wriggly’ enzymes that use movement to effect catalysis, it may be advantageous to have inhibitors that can maintain favourable contacts by adopting different tautomers as the enzyme ‘wriggles’. |
| وصف الملف: | application/pdf |
| تدمد: | 2059-7983 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c10065756a04a7d4296e9e123f9535b0 https://pubmed.ncbi.nlm.nih.gov/28177309 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....c10065756a04a7d4296e9e123f9535b0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20597983 |
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