Structural templates for modeling homodimers

Abstract

Oligomeric proteins are more abundant in nature than monomeric proteins, and involved in all biological processes. In the absence of an experimental structure, their subunits can be modeled from their sequence like monomeric proteins, but reliable procedures to build the oligomeric assembly are scarce. Template-based methods, which start from known protein structures, are commonly applied to model subunits. We present a method to model homodimers that relies on a structural alignment of the subunits, and test it on a set of 511 target structures recently released by the Protein Data Bank, taking as templates the earlier released structures of 3108 homodimeric proteins (H-set), and 2691 monomeric proteins that form dimer-like assemblies in crystals (M-set). The structural alignment identifies a H-set template for 97% of the targets, and in half of the cases, it yields a correct model of the dimer geometry and residue-residue contacts in the target. It also identifies a M-set template for most of the targets, and some of the crystal dimers are very similar to the target homodimers. The procedure efficiently detects homology at low levels of sequence identities, and points to erroneous quaternary structures in the Protein Data Bank. The high coverage of the target set suggests that the content of the Protein Data Bank already approaches the structural diversity of protein assemblies in nature, and that template-based methods should become the choice method for modeling oligomeric as well as monomeric proteins.

Modeling CAPRI targets 110‐120 by template‐based and free docking using contact potential and combined scoring function

“…All others were monomeric in both asymmetric and biological units. Thus, custom template library was built from the pairwise combinations of chains from the biounit and from PISA‐generated crystallographic interfaces of monomeric 4dot and 4dpz (details of the procedure are published elsewhere). For docking, we selected 11 CASP stage 2 models with the lowest AACE18 energies and the highest TM‐scores to the HHpred templates.…”

Template-based structure modeling of protein–protein interactions

“…However, the data resulting from such approaches also demonstrated a somewhat unexpected dependence on homologous templates, i.e. the majority of the successful docking models are for the targets with templates with a sequence identity >40% to the targets [22•,83], which partly reflects the inherent correlation between the evolutionary relationship and the structural similarity between different protein complexes.…”

Dockground: A comprehensive data resource for modeling of protein complexes

“…Simply selecting all pairwise complexes from PDB would result in many identical or highly similar complexes, leading to a very significant slow‐down of docking. The set would also contain erroneous, low‐quality, and non‐biological structures . Also, “static” sets of target and template structures would allow consistent comparison of the template‐based docking methodologies developed at different times, since comparing their performance on the evolving PDB may produce confusing results.…”

“…However, utilizing such a brute‐force set would tremendously increase computation time due to the presence of many identical or highly similar complexes. The set will also contain erroneous, low‐quality, and biologically irrelevant structures . Thus, groups working on structure alignment docking typically generate their own template libraries by filtering PDB in order to retain only the relevant interactions …”