Modelling covalent linkages in <i>CCP</i>4

Nicholls, Robert A.; Joosten, Robbie P.; Long, Fei; Wojdyr, Marcin; Лебедев, А. А.; Krissinel, Eugene; Catapano, Lucrezia; Fischer, Marcus; Emsley, Paul; Murshudov, Garib N.

doi:10.1107/s2059798321001753

Cited by 14 publications

(9 citation statements)

References 47 publications

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“…Currently, most refinement programs use a predefined set of restraints for common glycosidic linkages ( e.g ., α(1-2) or β(1-4)), but less-common linkages require newly generated restraints. To our knowledge, AceDRG is currently the only discussed restraint generator that has dedicated procedures for creating linkage restraints [ 47 ]. We will therefore focus on more general issues with restraints of glycosidic linkages.…”

Section: Resultsmentioning

confidence: 99%

Towards Consistency in Geometry Restraints for Carbohydrates in the Pyranose form: Modern Dictionary Generators Reviewed

Joosten

Nicholls

Agirre

2022

CMC

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: Macromolecular restrained refinement is nowadays the most used method for improving the agreement between an atomic structural model and experimental data. Restraint dictionaries, a key tool behind the success of the method, allow fine-tuning geometric properties such as distances and angles between atoms beyond simplistic expectations. Dictionary generators can provide restraint target estimates derived from different sources, from fully theoretical to experimental and any combination in between. Carbohydrates are stereochemically complex biomolecules and, in their pyranose form, have clear conformational preferences. As such, they pose unique problems to dictionary generators and in the course of this study, require special attention from software developers. Functional differences between restraint generators will be discussed, as well as the process of achieving consistent results with different software designs. The study will conclude a set of practical considerations, as well as recommendations for the generation of new restraint dictionaries, using the improved software alternatives discussed.

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Section: Resultsmentioning

confidence: 99%

Towards Consistency in Geometry Restraints for Carbohydrates in the Pyranose form: Modern Dictionary Generators Reviewed

Joosten

Nicholls

Agirre

2022

CMC

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“…Indeed, Gemmi can add link records to a model for all linkages of known type that are found using the link-finding algorithm (or otherwise). In addition to their use in the analyses presented in the subsequent subsections, these functionalities of Gemmi have also been utilized within graphical interfaces to facilitate the practical application of covalent linkages (Nicholls et al, 2021).…”

Section: Contact Analysis and Finding Potential Linkagesmentioning

confidence: 99%

“…For example, the link description with identifier 'NAG-SER' can be applied to any pyranose In such cases, where multiple dictionaries are available for a given residue pair, the one that is most specialized should be selected (subject to heuristic geometric configuration matching where relevant, for example trans/cis for peptide and / for glycosidic linkages). More recently, substantial efforts have gone into updating and extending the CCP4-ML in line with developments in AceDRG for the creation of component and link dictionaries (Long et al, 2017;Nicholls et al, 2021).…”

Section: Figurementioning

confidence: 99%

“…In this context, it should also be noted that there is a need to ensure cross-compatibility between different suites: the typical use of multiple tools from multiple suites should not result in a loss of information regarding provenance. In the CCP4 suite, linkage identifiers are currently specified using LINKR records in PDB format and using the ccp4_link_id data item in PDBx/mmCIF format models (Nicholls et al, 2021). However, looking to the future, we would encourage the adoption of a universal convention for the modelling of covalent linkages.…”

Section: Categorymentioning

confidence: 99%

“…However, since manual consideration is required in order to ensure that linkage descriptions correspond to appropriate chemistries, it has been deemed prudent to prioritize the addition of descriptions for linkage types that most commonly occur in the PDB. Link records (LINK/LINKR/struct_conn; see Nicholls et al, 2021) are essential during the model-building and refinement process (for nonpolymeric linkages). However, the deposition of link records is not considered to be mandatory.…”

Section: Introductionmentioning

confidence: 99%

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The missing link: covalent linkages in structural models

Nicholls¹,

Wojdyr²,

Joosten³

et al. 2021

Acta Crystallogr D Struct Biol

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Covalent linkages between constituent blocks of macromolecules and ligands have been subject to inconsistent treatment during the model-building, refinement and deposition process. This may stem from a number of sources, including difficulties with initially detecting the covalent linkage, identifying the correct chemistry, obtaining an appropriate restraint dictionary and ensuring its correct application. The analysis presented herein assesses the extent of problems involving covalent linkages in the Protein Data Bank (PDB). Not only will this facilitate the remediation of existing models, but also, more importantly, it will inform and thus improve the quality of future linkages. By considering linkages of known type in the CCP4 Monomer Library (CCP4-ML), failure to model a covalent linkage is identified to result in inaccurate (systematically longer) interatomic distances. Scanning the PDB for proximal atom pairs that do not have a corresponding type in the CCP4-ML reveals a large number of commonly occurring types of unannotated potential linkages; in general, these may or may not be covalently linked. Manual consideration of the most commonly occurring cases identifies a number of genuine classes of covalent linkages. The recent expansion of the CCP4-ML is discussed, which has involved the addition of over 16 000 and the replacement of over 11 000 component dictionaries using AceDRG. As part of this effort, the CCP4-ML has also been extended using AceDRG link dictionaries for the aforementioned linkage types identified in this analysis. This will facilitate the identification of such linkage types in future modelling efforts, whilst concurrently easing the process involved in their application. The need for a universal standard for maintaining link records corresponding to covalent linkages, and references to the associated dictionaries used during modelling and refinement, following deposition to the PDB is emphasized. The importance of correctly modelling covalent linkages is demonstrated using a case study, which involves the covalent linkage of an inhibitor to the main protease in various viral species, including SARS-CoV-2. This example demonstrates the importance of properly modelling covalent linkages using a comprehensive restraint dictionary, as opposed to just using a single interatomic distance restraint or failing to model the covalent linkage at all.

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