DaReUS-Loop: accurate loop modeling using fragments from remote or unrelated proteins

Abstract

Despite efforts during the past decades, loop modeling remains a difficult part of protein structure modeling. Several approaches have been developed in the framework of crystal structures. However, for homology models, the modeling of loops is still far from being solved. We propose DaReUS-Loop, a data-based approach that identifies loop candidates mining the complete set of experimental structures available in the Protein Data Bank. Candidate filtering relies on local conformation profile-profile comparison, together with physico-chemical scoring. Applied to three different template-based test sets, DaReUS-Loop shows significant increase in the number of high-accuracy loops, and significant enhancement for modeling long loops. A special advantage is that our method proposes a prediction confidence score that correlates well with the expected accuracy of the loops. Strikingly, over 50% of successful loop models are derived from unrelated proteins, indicating that fragments under similar constraints tend to adopt similar structure, beyond mere homology.

Identification of peptides interfering with the LRRK2/PP1 interaction

“…The comparative modelling of the LRRK2 domain was done using the hhsearch suite[ 23 ] to identify a possible 3D template of the Protein Data Bank[ 24 ] 3D modelling was performed using as template the 3DPT PDB entry and the Tito software[ 25 ] to refine the hhsearch alignment, and identify preserved regions of the template. Loops were then built using the DaReUS-loop approach[ 26 ].…”

Structural proteomics, electron cryo-microscopy and structural modeling approaches in bacteria–human protein interactions

“…In this category, some of the popular softwares are RosettaCM [82], Modeler [83], HHpred [84], and I-TASSER [85]. In addition to the aforementioned methods, models or low-resolution experimental data from NMR or X-ray crystallography can be improved and refined by several computational techniques such as loop-modeling approaches like next-generation KIC (NGK) [86], and DaReUS-Loop [87,88] or experimental data-based protocols of Rosetta such as RosettaES [89], CS-Rosetta [90], and RosettaNMR [91].…”

Structural determination ofStreptococcus pyogenesM1 protein interactions with human immunoglobulin G using integrative structural biology

“…Using Rosetta Software suit [17], comparative models have been generated for human IgG subclasses based on crystal structures deposited in protein data bank with PDB IDs 1hzh, 4haf, 5w38, and 4c54 for IgG1, IgG2, IgG3, and IgG4, respectively. For IgG1, we modeled the gap in the hinge region using DaReUS-Loop [18,19], re-packed the sidechains of the full structure, and made the final set of models with rosetta relax protocol considering the disulfide bridges as the input constraints.…”