Conformation Dependence of Backbone Geometry in Proteins

By D. Berkholz, Maxim V. Shapovalov, Roland L. Dunbrack, Paul Karplus. 2009

108 citations recorded by the source corpus.

Summary Protein structure determination and predictive modeling have long been guided by the paradigm that the peptide backbone has a single, context-independent ideal geometry. Both quantum-mechanics calculations and empirical analyses have shown this is an incorrect simplification in that backbone covalent geometry actually varies systematically as a function of the Φ and Ψ backbone dihedral angles. Here, we use a nonredundant set of ultrahigh-resolution protein structures to define these conformation-dependent variations. The trends have a rational, structural basis that can be explained by avoidance of atomic clashes or optimization of favorable electrostatic interactions. To facilitate adoption of this new paradigm, we have created a conformation-dependent library of covalent bond lengths and bond angles and shown that it has improved accuracy over existing methods without any additional variables to optimize. Protein structures derived both from crystallographic refinement and predictive modeling both stand to benefit from incorporation of the new paradigm.

Subfields: Materials Chemistry, Molecular Biology, Pharmacology

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Citations in the corpus

Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix (2019, methodology): “Recent additions to the restraints used in Phenix include the conformation-dependent library (Berkholz et al., 2009; Moriarty et al., 2014, 2016), which restrains the protein main chain as a function of the backbone dihedral values.”
Model validation: local diagnosis, correction and when to quit (2018, background): “They have been updated primarily by making them context-dependent: on ’, by Karplus and Dunbrack (Berkholz et al., 2009), on ribose pucker by us (Jain et al., 2015) or by combining angles into the C deviation, which flags a C position forced to be nontetrahedral by an incorrect local fit of either…”
A fresh look at the Ramachandran plot and the occurrence of standard structures in proteins (2010, background): “(23) have followed up that work to show that in all regions of the Ramachandran plot, the expected ‘ideal’ bond angles vary in a way that makes sense to optimize non-covalent interactions.”
RosettaAntibodyDesign (RAbD): A general framework for computational antibody design (2017, background): “5 Å and both the Cα-C-N and C-N-Cα angles are less then 15 degrees away from the ideal min and max values determined by Berkholz et al.[97] (114.”
Conformation-dependent backbone geometry restraints set a new standard for protein crystallographic refinement (2014, methodology): “…conformation, and, as a first step towards using such information to build more accurate models, ultra-high-resolution protein crystal structures have been used to derive a conformation-dependent library (CDL) of restraints for the protein backbone [Berkholz et al. (2009) Structure 17, 1316–1325].”
A new default restraint library for the protein backbone in Phenix: a conformation-dependent geometry goes mainstream (2016, background): “Shortly thereafter, an analysis was carried out that codified how backbone bond lengths and angles were observed to change with conformation in a large set of protein crystal structures solved at 1 Å resolution or better (Berkholz et al., 2009).”
A New Generation of Crystallographic Validation Tools for the Protein Data Bank (2011, background): “C) shows a bimodal distribution depending on the secondary structure (Berkholz et al., 2009), several bond angles at the ribose ring are bimodal between C3 0 -endo and C2 0 -endo ring puckers (Gelbin et al., 1996), and some side-chain rotamers require a widening of bond angles at C a and C b…”
An editor for the generation and customization of geometry restraints (2017, background): “…are becoming standard practice in structure refinement: single-value restraints have been shown to be inadequate for the protein backbone, and the Conformation Dependent Library (CDL; Berkholz et al., 2009) has recently been made the default in phenix.refine (Moriarty et al., 2014, 2016).”