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What are the current limits on determination of protonation state using neutron macromolecular crystallography?

ABSTRACT: The rate of deposition of models determined by neutron diffraction, or a hybrid approach that combines X-ray and neutron diffraction, has increased in recent years. The benefit of neutron diffraction is that hydrogen atom (H) positions are detectable, allowing for the determination of protonation state and water molecule orientation. This study analyses all neutron models deposited in the Protein Data Bank to date, focusing on protonation state and properties of H (or deuterium, D) atoms as well as the details of water molecules. In particular, clashes and hydrogen bonds involving H or D atoms are investigated. As water molecules are typically the least reproducible part of a structural model, their positions in neutron models were compared to those in homologous high-resolution X-ray structures. For models determined by joint refinement against X-ray and neutron data, the water structure comparison was also carried out for models re-refined against the X-ray data alone. The homologues have generally fewer conserved water molecules where X-ray only was used and the positions of equivalent waters vary more than in the case of the hybrid X-ray model. As neutron diffraction data are generally less complete than X-ray data, the influence of neutron data completeness on nuclear density maps was also analyzed. We observe and discuss systematic map quality deterioration as result of data incompleteness.

SUBMITTER: Liebschner D

PROVIDER: S-EPMC7571246 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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What are the current limits on determination of protonation state using neutron macromolecular crystallography?

Liebschner Dorothee D Afonine Pavel V PV Moriarty Nigel W NW Adams Paul D PD

Methods in enzymology 20200213

The rate of deposition of models determined by neutron diffraction, or a hybrid approach that combines X-ray and neutron diffraction, has increased in recent years. The benefit of neutron diffraction is that hydrogen atom (H) positions are detectable, allowing for the determination of protonation state and water molecule orientation. This study analyses all neutron models deposited in the Protein Data Bank to date, focusing on protonation state and properties of H (or deuterium, D) atoms as well ...[more]

PMID: 32093835

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Project description:Gaining an understanding of the protein-ligand complex structure along with the proper protonation and explicit solvent effects can be important in obtaining meaningful results in structure-guided drug discovery and structure-based drug discovery. Unfortunately, protonation and tautomerism are difficult to establish with conventional methods because of difficulties in the experimental detection of H atoms owing to the well known limitations of X-ray crystallography. In the present work, it is demonstrated that semiempirical, quantum-mechanics-based macromolecular crystallographic refinement is sensitive to the choice of a protonation-state/tautomer form of ligands and residues, and can therefore be used to explore potential states. A novel scoring method, called XModeScore, is described which enumerates the possible protomeric/tautomeric modes, refines each mode against X-ray diffraction data with the semiempirical quantum-mechanics (PM6) Hamiltonian and scores each mode using a combination of energetic strain (or ligand strain) and rigorous statistical analysis of the difference electron-density distribution. It is shown that using XModeScore it is possible to consistently distinguish the correct bound protomeric/tautomeric modes based on routine X-ray data, even at lower resolutions of around 3 Å. These X-ray results are compared with the results obtained from much more expensive and laborious neutron diffraction studies for three different examples: tautomerism in the acetazolamide ligand of human carbonic anhydrase II (PDB entries 3hs4 and 4k0s), tautomerism in the 8HX ligand of urate oxidase (PDB entries 4n9s and 4n9m) and the protonation states of the catalytic aspartic acid found within the active site of an aspartic protease (PDB entry 2jjj). In each case, XModeScore applied to the X-ray diffraction data is able to determine the correct protonation state as defined by the neutron diffraction data. The impact of QM-based refinement versus conventional refinement on XModeScore is also discussed.

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What are the current limits on determination of protonation state using neutron macromolecular crystallography?

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What are the current limits on determination of protonation state using neutron macromolecular crystallography?

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