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Review
. 2017 Feb 1;73(Pt 2):93-102.
doi: 10.1107/S2059798316017964. Epub 2017 Feb 1.

Keep it together: restraints in crystallographic refinement of macromolecule-ligand complexes

Roberto A Steiner  1 , Julie A Tucker  2
Affiliations
Review

Keep it together: restraints in crystallographic refinement of macromolecule-ligand complexes

Roberto A Steiner et al. Acta Crystallogr D Struct Biol. .

Abstract

A short introduction is provided to the concept of restraints in macromolecular crystallographic refinement. A typical ligand restraint-generation process is then described, covering types of input, the methodology and the mechanics behind the software in general terms, how this has evolved over recent years and what to look for in the output. Finally, the currently available restraint-generation software is compared, concluding with some thoughts for the future.

Keywords: ligand complexes; macromolecular crystallography; refinement; restraint sets; standard deviation.

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Figures

Figure 1
Figure 1
Schematic of the dictionary-generation process.
Figure 2
Figure 2
Types of input to a dictionary generator, illustrated using a hypothetical example molecule, chimerin1. Chimerin1 may be described using a two-dimensional sketch (a), as a SMILES string of different types (b, c) or as a set of coordinates, illustrated here in PDB format both without (d) and with (e) CONECT records. Restraint types are illustrated in (a): a bond-length restraint between two atoms (i), a bond-angle restraint between three bonded atoms (ii), a dihedral restraint relating four atoms (iii), a chiral restraint (iv) and a planar restraint (v). (a)–(c) were prepared using ChemBioDraw Ultra 14.0 (PerkinElmer) and (d) and (e) using ACEDRG (Long et al., 2017 ▸) to generate coordinates and CCP4mg (McNicholas et al., 2011 ▸) for rendering.
Figure 3
Figure 3
Comparison of output coordinates from selected dictionary generators: (a) ACEDRG, (b) astex_prepare_dictionary, (c) Corina, (d) phenix.elbow, (e) grade, (f) PRODRG2, (g) Pyrogen, (h) writedict and (i) Libcheck. Coordinates were overlaid using the Superpose Ligand function in Coot (Debreczeni & Emsley, 2012 ▸), with minor manual adjustment if required, and then displayed and rendered using CCP4mg (McNicholas et al., 2011 ▸).
Figure 4
Figure 4
Comparison of output coordinates from selected dictionary generators (a, c) before and (b, c) after idealization. (a) Overlay of output coordinates from selected dictionary generators (Figs. 3 ▸ a–3 ▸ h), aligned and coloured as in Fig. 3 ▸. Libcheck (Fig. 3 ▸ i) has been omitted for the sake of clarity. Overlay of coordinates from (b) phenix.elbow and (c) Libcheck before (C atoms coloured cyan) and after (C atoms coloured pink) idealization in REFMAC5.
Figure 5
Figure 5
Comparison of bond restraints from selected dictionary generators. Bond-length restraints assigned by program A on the vertical axis are plotted in Å against those assigned by program B on the horizontal axis. Each matched pair is represented by a dot, where bonds between two C atoms are coloured black and those containing at least one N atom are blue, O atom red, S atom gold, P atom dark orange and halogen (Cl, Br, F or I atom) green. For a more complete description of the methodology underlying this figure, please see §S5 of the Supporting Information.
Figure 6
Figure 6
Variation in dictionary-generator standard deviations (e.s.d.) for a selected bond length (Br—C8) (a) and bond angle (Br—C8—C7) (b) in chimerin1. Atoms are numbered as shown in Fig. 2 ▸(d). The standard deviation for all bonds/angles of that type in the CSD obtained using Mogul is highlighted as a dashed line.
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