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Pathological macromolecular crystallographic data affected by twinning, partial-disorder and exhibiting multiple lattices for testing of data processing and refinement tools.

ABSTRACT: Twinning is a crystal growth anomaly, which has posed a challenge in macromolecular crystallography (MX) since the earliest days. Many approaches have been used to treat twinned data in order to extract structural information. However, in most cases it is usually simpler to rescreen for new crystallization conditions that yield an untwinned crystal form or, if possible, collect data from non-twinned parts of the crystal. Here, we report 11 structures of engineered variants of the E. coli enzyme N-acetyl-neuraminic lyase which, despite twinning and incommensurate modulation, have been successfully indexed, solved and deposited. These structures span a resolution range of 1.45-2.30?Å, which is unusually high for datasets presenting such lattice disorders in MX and therefore these data provide an excellent test set for improving and challenging MX data processing programs.

SUBMITTER: Campeotto I

PROVIDER: S-EPMC6173773 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Pathological macromolecular crystallographic data affected by twinning, partial-disorder and exhibiting multiple lattices for testing of data processing and refinement tools.

Campeotto Ivan I Lebedev Andrey A Schreurs Antoine M M AMM Kroon-Batenburg Loes M J LMJ Lowe Edward E Phillips Simon E V SEV Murshudov Garib N GN Pearson Arwen R AR

Scientific reports 20181005 1

Twinning is a crystal growth anomaly, which has posed a challenge in macromolecular crystallography (MX) since the earliest days. Many approaches have been used to treat twinned data in order to extract structural information. However, in most cases it is usually simpler to rescreen for new crystallization conditions that yield an untwinned crystal form or, if possible, collect data from non-twinned parts of the crystal. Here, we report 11 structures of engineered variants of the E. coli enzyme ...[more]

PMID: 30291262

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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.

Dataset Information

Pathological macromolecular crystallographic data affected by twinning, partial-disorder and exhibiting multiple lattices for testing of data processing and refinement tools.

Publications

Pathological macromolecular crystallographic data affected by twinning, partial-disorder and exhibiting multiple lattices for testing of data processing and refinement tools.

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