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

2016 ◽  
Vol 72 (4) ◽  
pp. 586-598 ◽  
Author(s):  
Oleg Borbulevych ◽  
Roger I. Martin ◽  
Ian J. Tickle ◽  
Lance M. Westerhoff
Keyword(s):  
Quantum Mechanics ◽  
Drug Discovery ◽  
Neutron Diffraction ◽  
Diffraction Data ◽  
Complex Structure ◽  
Urate Oxidase ◽  
X Ray Diffraction ◽  
Protonation State ◽  
X Ray ◽  
The Impact

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, calledXModeScore, 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 usingXModeScoreit 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,XModeScoreapplied 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 refinementversusconventional refinement onXModeScoreis also discussed.

scholarly journals Accurate H-atom parameters for the two polymorphs of L-histidine at 5, 105 and 295 K

2021 ◽  
Vol 77 (5) ◽  
pp. 785-800
Author(s):  
Giulia Novelli ◽  
Charles J. McMonagle ◽  
Florian Kleemiss ◽  
Michael Probert ◽  
Horst Puschmann ◽  
...  
Keyword(s):  
Neutron Diffraction ◽  
Single Crystal ◽  
Diffraction Data ◽  
Crystal Packing ◽  
Basis Sets ◽  
X Ray Diffraction ◽  
X Ray ◽  
Refinement Method ◽  
Primary Amino ◽  
Precision And Accuracy

The crystal structure of the monoclinic polymorph of the primary amino acid L-histidine has been determined for the first time by single-crystal neutron diffraction, while that of the orthorhombic polymorph has been reinvestigated with an untwinned crystal, improving the experimental precision and accuracy. For each polymorph, neutron diffraction data were collected at 5, 105 and 295 K. Single-crystal X-ray diffraction experiments were also performed at the same temperatures. The two polymorphs, whose crystal packing is interpreted by intermolecular interaction energies calculated using the Pixel method, show differences in the energy and geometry of the hydrogen bond formed along the c direction. Taking advantage of the X-ray diffraction data collected at 5 K, the precision and accuracy of the new Hirshfeld atom refinement method implemented in NoSpherA2 were probed choosing various settings of the functionals and basis sets, together with the use of explicit clusters of molecules and enhanced rigid-body restraints for H atoms. Equivalent atomic coordinates and anisotropic displacement parameters were compared and found to agree well with those obtained from the corresponding neutron structural models.

scholarly journals Glycyl-L-alanine: a multi-temperature neutron study

2014 ◽  
Vol 70 (10) ◽  
pp. 949-952 ◽  
Author(s):  
Silvia C. Capelli ◽  
Hans-Beat Bürgi ◽  
Sax A. Mason ◽  
Dylan Jayatilaka
Keyword(s):  
Hydrogen Bonding ◽  
Neutron Diffraction ◽  
Diffraction Data ◽  
Neutron Diffraction Data ◽  
X Ray Diffraction ◽  
X Ray ◽  
Hydrogen Bonding Interactions ◽  
Anisotropic Displacement Parameters

Neutron diffraction data have been collected at 12, 50, 150 and 295 K for the dipeptide glycyl-L-alanine, C5H10N2O3, in order to obtain accurate positional and anisotropic displacement parameters for the H atoms. The values of these parameters serve as a benchmark for assessing the equivalent parameters obtained from a so-called Hirshfeld-atom refinement of X-ray diffraction data described elsewhere [Capelliet al.(2014).IUCrJ,1, 361–379]. The flexibility of the glycyl-L-alanine molecule in the solid and the hydrogen-bonding interactions as a function of temperature are also considered.

Crystal chemistry and nomenclature of fillowite-type phosphates

2021 ◽  
Vol 59 (4) ◽  
pp. 781-796
Author(s):  
Frédéric Hatert ◽  
Edward S. Grew ◽  
Pietro Vignola ◽  
Nicola Rotiroti ◽  
Fabrizio Nestola ◽  
...  
Keyword(s):  
Diffraction Data ◽  
Divalent Cations ◽  
Complex Structure ◽  
Asymmetric Unit ◽  
X Ray Diffraction ◽  
Unit Cell Parameters ◽  
X Ray ◽  
Cell Parameters ◽  
Cation Sites ◽  
Cation Distributions

ABSTRACT The crystal chemistries of five samples of minerals belonging to the fillowite group were structurally investigated: (A) fillowite from the Buranga pegmatite, Rwanda; (B) fillowite from the Kabira pegmatite, Uganda; (C) johnsomervilleite from Loch Quoich, Scotland; (D) johnsomervilleite from the Malpensata pegmatite, Italy; and (E) chladniite from the Sapucaia pegmatite, Minas Gerais, Brazil. Their crystal structures were refined in space group R (No. 148), using single-crystal X-ray diffraction data, to R1 values of (A) 3.79%, (B) 3.52%, (C) 4.14%, (D) 4.04%, and (E) 5.59%. Unit-cell parameters are: (A) a = 15.122(1), c = 43.258(4) Å; (B) a = 15.125(1), c = 43.198(3) Å; (C) a = 15.036(2), c = 42.972(9) Å; (D) a = 15.090(2), c = 43.050(9) Å; and (E) a = 15.1416(6), c = 43.123(2) Å. The asymmetric unit contains 15 cation sites with coordinations ranging from V to IX, as well as six P sites. The complex structure can be split into three types of chains running parallel to the c axis. These chains are composed of edge- and face-sharing polyhedra. Detailed cation distributions were determined for all five samples, and their comparison allowed us to establish the general formula A3BC11(PO4)9 for fillowite-type phosphates, where A represents the group of sites mainly occupied by Na, B the Ca sites, and C the sites containing the divalent cations Fe2+, Mn, and Mg. This formula was accepted by the CNMNC, and the four valid mineral species occurring in the fillowite group are fillowite (C = Mn), johnsomervilleite (C = Fe2+), chladniite (C = Mg), and galileiite (B and C = Fe2+). Stornesite-(Y) is discredited, since this mineral corresponds to Y-bearing chladniite.

TAAM: a reliable and user friendly tool for hydrogen-atom location using routine X-ray diffraction data

2020 ◽  
Vol 76 (3) ◽  
pp. 296-306 ◽  
Author(s):  
Kunal Kumar Jha ◽  
Barbara Gruza ◽  
Prashant Kumar ◽  
Michal Leszek Chodkiewicz ◽  
Paulina Maria Dominiak
Keyword(s):  
Neutron Diffraction ◽  
Diffraction Data ◽  
Structure Refinement ◽  
X Rays ◽  
X Ray Diffraction ◽  
Hydrogen Atoms ◽  
X Ray ◽  
Bond Lengths ◽  
Atom Model ◽  
User Friendly

Hydrogen is present in almost all of the molecules in living things. It is very reactive and forms bonds with most of the elements, terminating their valences and enhancing their chemistry. X-ray diffraction is the most common method for structure determination. It depends on scattering of X-rays from electron density, which means the single electron of hydrogen is difficult to detect. Generally, neutron diffraction data are used to determine the accurate position of hydrogen atoms. However, the requirement for good quality single crystals, costly maintenance and the limited number of neutron diffraction facilities means that these kind of results are rarely available. Here it is shown that the use of Transferable Aspherical Atom Model (TAAM) instead of Independent Atom Model (IAM) in routine structure refinement with X-ray data is another possible solution which largely improves the precision and accuracy of X—H bond lengths and makes them comparable to averaged neutron bond lengths. TAAM, built from a pseudoatom databank, was used to determine the X—H bond lengths on 75 data sets for organic molecule crystals. TAAM parametrizations available in the modified University of Buffalo Databank (UBDB) of pseudoatoms applied through the DiSCaMB software library were used. The averaged bond lengths determined by TAAM refinements with X-ray diffraction data of atomic resolution (d min ≤ 0.83 Å) showed very good agreement with neutron data, mostly within one single sample standard deviation, much like Hirshfeld atom refinement (HAR). Atomic displacements for both hydrogen and non-hydrogen atoms obtained from the refinements systematically differed from IAM results. Overall TAAM gave better fits to experimental data of standard resolution compared to IAM. The research was accompanied with development of software aimed at providing user-friendly tools to use aspherical atom models in refinement of organic molecules at speeds comparable to routine refinements based on spherical atom model.

scholarly journals A Neutron and X-ray Diffraction Study of the Structure of Nd Phosphate Glasses

2001 ◽  
Vol 56 (3-4) ◽  
pp. 237-243 ◽  
Author(s):  
Uwe Hoppe ◽  
Heike Ebendorff-Heidepriem ◽  
Jörg Neuefeind ◽  
Daniel T. Bowron
Keyword(s):  
Neutron Diffraction ◽  
Diffraction Study ◽  
Coordination Number ◽  
Diffraction Data ◽  
Phosphate Glasses ◽  
Neutron Diffraction Data ◽  
X Ray Diffraction ◽  
X Ray ◽  
Oxygen Atoms

Abstract Diffraction experiments were performed on two (Nd2O3)x(P2O5)1- x glasses for studying the en­ vironmental order of the Nd3+ cations. In case of the metaphosphate glass (x = 0.25) a combination of X-ray and neutron diffraction data was used to separate the Nd-O and O-O first neighbor peaks. An Nd-O coordination number of 6.6±0.3 and a mean Nd-O distance of (0.239±0.001) nm were determined. In the ultraphosphate glass studied (x = 0.20) these values increase to 6.9±0.3 and (0.240±0.001) nm where the Nd-0 coordination number is equal to the number of terminal oxygen atoms (OT) which are available for coordination of each Nd3+ cation. This indicates the formation of NdOn polyhedra not sharing any O atom where also all OT's are in N d-OT-P positions. In the metaphosphate glass the NdOn polyhedra have to share some OT sites.

Atomic displacement parameters for Ni(ND3)4(NO2)2 from 9 K X-ray and 13 K time-of-flight neutron diffraction data

1996 ◽  
Vol 52 (6) ◽  
pp. 923-931 ◽  
Author(s):  
B. B. Iversen ◽  
F. K. Larsen ◽  
B. N. Figgis ◽  
P. A. Reynolds ◽  
A. J. Schultz
Keyword(s):  
Neutron Diffraction ◽  
Diffraction Data ◽  
Structural Information ◽  
Structural Parameters ◽  
Structure Refinement ◽  
Time Of Flight ◽  
Thermal Parameters ◽  
Neutron Diffraction Data ◽  
X Ray Diffraction ◽  
X Ray

Structural parameters derived from 9 1) K X-ray diffraction data and 13 (1) K time-of-flight neutron diffraction data on perdeuterated tetraamminedinitronickel(II), Ni(ND3)4(NO2)2, are compared. It is shown that excellent agreement can be obtained for both positional and thermal parameters derived separately from the two experiments, provided that great care is taken in all steps of the process, including data collection, data reduction, and nuclear and electronic structure refinement. The mean difference in the thermal parameters, <|ΔUij |>, is as low as 0.00034 Å2 and <(ΔUij/σ)2>1/2 = 1.92, showing that, even without any form of scaling between the parameters, the same values can be obtained. This, compared with other such studies, indicates that time-of-flight neutron diffraction data can give structural information of a quality comparable to monochromatic neutron diffraction. The excellent correspondence between the thermal parameters derived separately from X-ray and neutron diffraction data gives confidence in the deconvolution of the thermal motion from the X-ray diffraction data, which is necessary for any study of a static electron density distribution.

Opening and Narrowing of the Water H—O—H Angle by Hydrogen-Bonding Effects: Re-inspection of Neutron Diffraction Data

1998 ◽  
Vol 54 (4) ◽  
pp. 464-470 ◽  
Author(s):  
T. Steiner
Keyword(s):  
Hydrogen Bonding ◽  
Hydrogen Bonds ◽  
Neutron Diffraction ◽  
Diffraction Data ◽  
Water Molecules ◽  
Hydroxyl Groups ◽  
Secondary Effects ◽  
X Ray Diffraction ◽  
X Ray ◽  
Sample Average

For 71 water molecules donating two Ow—H...O hydrogen bonds, the correlation of the covalent H—O—H angle and the O...Ow...O angle is inspected from 49 well refined organic and organometallic neutron diffraction crystal structures. Compared to sample average, the water angle is opened for large and narrowed for small O...Ow...O angles. Notably, the H—O—H angle is widened compared with the gas phase value even for small O...Ow...O. Related behavior is observed for chloride anion acceptors. The correlation exhibits a considerable scatter which should not be interpreted as experimental inaccuracies, but as secondary effects. Possible secondary effects are multi-center hydrogen bonding and effects of coordination to the water O atom. In a comparative test, low-temperature X-ray diffraction data were shown to be completely unsuitable for this type of analysis. The dependence of the C—O—H angle on the C—O...O angle in hydrogen bonds donated by hydroxyl groups in carbohydrates is also shown.

Sign in / Sign up

Export Citation Format

Share Document