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XModeScore: a novel method for accurate protonation/tautomer-state determination using quantum-mechanically driven macromolecular X-ray crystallographic refinement

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 diffi...

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Autores principales: Borbulevych, Oleg, Martin, Roger I., Tickle, Ian J., Westerhoff, Lance M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: International Union of Crystallography 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822566/
https://www.ncbi.nlm.nih.gov/pubmed/27050137
http://dx.doi.org/10.1107/S2059798316002837
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author Borbulevych, Oleg
Martin, Roger I.
Tickle, Ian J.
Westerhoff, Lance M.
author_facet Borbulevych, Oleg
Martin, Roger I.
Tickle, Ian J.
Westerhoff, Lance M.
author_sort Borbulevych, Oleg
collection PubMed
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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spelling pubmed-48225662016-04-28 XModeScore: a novel method for accurate protonation/tautomer-state determination using quantum-mechanically driven macromolecular X-ray crystallographic refinement Borbulevych, Oleg Martin, Roger I. Tickle, Ian J. Westerhoff, Lance M. Acta Crystallogr D Struct Biol Research Papers 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. International Union of Crystallography 2016-03-30 /pmc/articles/PMC4822566/ /pubmed/27050137 http://dx.doi.org/10.1107/S2059798316002837 Text en © Borbulevych et al. 2016 http://creativecommons.org/licenses/by/2.0/uk/ This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.
spellingShingle Research Papers
Borbulevych, Oleg
Martin, Roger I.
Tickle, Ian J.
Westerhoff, Lance M.
XModeScore: a novel method for accurate protonation/tautomer-state determination using quantum-mechanically driven macromolecular X-ray crystallographic refinement
title XModeScore: a novel method for accurate protonation/tautomer-state determination using quantum-mechanically driven macromolecular X-ray crystallographic refinement
title_full XModeScore: a novel method for accurate protonation/tautomer-state determination using quantum-mechanically driven macromolecular X-ray crystallographic refinement
title_fullStr XModeScore: a novel method for accurate protonation/tautomer-state determination using quantum-mechanically driven macromolecular X-ray crystallographic refinement
title_full_unstemmed XModeScore: a novel method for accurate protonation/tautomer-state determination using quantum-mechanically driven macromolecular X-ray crystallographic refinement
title_short XModeScore: a novel method for accurate protonation/tautomer-state determination using quantum-mechanically driven macromolecular X-ray crystallographic refinement
title_sort xmodescore: a novel method for accurate protonation/tautomer-state determination using quantum-mechanically driven macromolecular x-ray crystallographic refinement
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822566/
https://www.ncbi.nlm.nih.gov/pubmed/27050137
http://dx.doi.org/10.1107/S2059798316002837
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