Dataset Information

Protoss: a holistic approach to predict tautomers and protonation states in protein-ligand complexes.

ABSTRACT: The calculation of hydrogen positions is a common preprocessing step when working with crystal structures of protein-ligand complexes. An explicit description of hydrogen atoms is generally needed in order to analyze the binding mode of particular ligands or to calculate the associated binding energies. Due to the large number of degrees of freedom resulting from different chemical moieties and the high degree of mutual dependence this problem is anything but trivial. In addition to an efficient algorithm to take care of the complexity resulting from complicated hydrogen bonding networks, a robust chemical model is needed to describe effects such as tautomerism and ionization consistently. We present a novel method for the placement of hydrogen coordinates in protein-ligand complexes which takes tautomers and protonation states of both protein and ligand into account. Our method generates the most probable hydrogen positions on the basis of an optimal hydrogen bonding network using an empirical scoring function. The high quality of our results could be verified by comparison to the manually adjusted Astex diverse set and a remarkably low rate of undesirable hydrogen contacts compared to other tools.

SUBMITTER: Bietz S

PROVIDER: S-EPMC4019353 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Protoss: a holistic approach to predict tautomers and protonation states in protein-ligand complexes.

Bietz Stefan S Urbaczek Sascha S Schulz Benjamin B Rarey Matthias M

Journal of cheminformatics 20140403

The calculation of hydrogen positions is a common preprocessing step when working with crystal structures of protein-ligand complexes. An explicit description of hydrogen atoms is generally needed in order to analyze the binding mode of particular ligands or to calculate the associated binding energies. Due to the large number of degrees of freedom resulting from different chemical moieties and the high degree of mutual dependence this problem is anything but trivial. In addition to an efficient ...[more]

PMID: 24694216

Similar Datasets

Project description: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'.

Dataset Information

Protoss: a holistic approach to predict tautomers and protonation states in protein-ligand complexes.

Publications

Protoss: a holistic approach to predict tautomers and protonation states in protein-ligand complexes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets