ProteinFishing: a protein complex generator within the ModelX toolsuite

Abstract

Summary Accurate 3D modelling of protein–protein interactions (PPI) is essential to compensate for the absence of experimentally determined complex structures. Here, we present a new set of commands within the ModelX toolsuite capable of generating atomic-level protein complexes suitable for interface design. Among these commands, the new tool ProteinFishing proposes known and/or putative alternative 3D PPI for a given protein complex. The algorithm exploits backbone compatibility of protein fragments to generate mutually exclusive protein interfaces that are quickly evaluated with a knowledge-based statistical force field. Using interleukin-10-R2 co-crystalized with interferon-lambda-3, and a database of X-ray structures containing interleukin-10, this algorithm was able to generate interleukin-10-R2/interleukin-10 structural models in agreement with experimental data. Availability and implementation ProteinFishing is a portable command-line tool included in the ModelX toolsuite, written in C++, that makes use of an SQL (tested for MySQL and MariaDB) relational database delivered with a template SQL dump called FishXDB. FishXDB contains the empty tables of ModelX fragments and the data used by the embedded statistical force field. ProteinFishing is compiled for Linux-64bit, MacOS-64bit and Windows-32bit operating systems. This software is a proprietary license and is distributed as an executable with its correspondent database dumps. It can be downloaded publicly at http://modelx.crg.es/. Licenses are freely available for academic users after registration on the website and are available under commercial license for for-profit organizations or companies. Supplementary information Supplementary data are available at Bioinformatics online.

Bacterial expression of a designed single‐chain IL ‐10 prevents severe lung inflammation

“…Here, we (i) designed mutations in IL‐10 that increase its affinity for the R1 and R2 receptors (Gorby et al , 2020 ) and (ii) engineered a single‐chain (SC) variant composed of two IL‐10 monomers, using two protein design softwares: FoldX (Schymkowitz et al , 2005 ; Delgado et al , 2019 ) and ModelX (Blanco et al , 2018 ; Delgado Blanco et al , 2019 ; Cianferoni et al , 2020 ). MPN was able to express active IL‐10 and the new IL‐10 variants that exhibited an increased affinity as compared to the wild‐type (WT) IL‐10 (IL‐10 ORF) in vitro and had a powerful antiinflammatory effect in an acute lung infection model induced by Pseudomonas aeruginosa .…”

Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple‐negative breast cancer

“…To propose binding models between BRD4 bromodomains 1 and 2 (BD1 and BD2) and LOXL2, we performed a docking analysis of BRD4_BD1/LOXL2 and BRD4_BD2/LOXL2. We used a collection of structures (Table EV1) from the Protein Data Bank (Berman et al , 2000) (PDB) and Interactome3d (Mosca et al , 2013), and three independent software programs, ZDOCK (Pierce et al , 2014), Autodock VINA (Trott & Olson, 2010), and ProteinFishing (Cianferoni et al , 2020). The results were energetically minimized and ranked based on the buried surface, FoldX (Delgado et al , 2019) interaction energy, and FoldX (Delgado et al , 2019) stability.…”

“…The first group of structures, together with the only available PDB model for LOXL2 (5ZE3), was used to run docking on the ZDOCK server (Pierce et al , 2014) and Autodock VINA (Trott & Olson, 2010). Models capturing BRD4 in interactions were used as input for ProteinFishing (Cianferoni et al , 2020) together with the LOXL2 structure. The obtained models were later minimized using the YASARA structure minimization routine, followed by the FoldX RepairPDB .…”

The BRD4S-LOXL2-MED1 interaction at the forefront of cell cycle transcriptional control in triple-negative breast cancer

“…Finally, we performed a docking analysis of BRD4_BD1/LOXL2 and BRD4_BD2/LOXL2, respectively. A collection of structures ( table S1 ) from the Protein Data Bank ( 38 ) (PDB) and Interactome3d ( 39 ), and three independent software (ZDOCK ( 40 ), Autodock VINA ( 41 ), and ProteinFishing ( 42 )) were used to propose binding models. Results were energetically minimized and ranked based on buried surface, FoldX ( 43 ) interaction energy, and FoldX ( 43 ) stability.…”

“…The first group of structures, together with the only available PDB model for LOXL2 (5ZE3), served to run docking on the ZDOCK server ( 40 ) and Autodock VINA ( 41 ). Models capturing BRD4 into interactions were used as input for ProteinFishing ( 42 ) together with the LOXL2 structure. Obtained models were later minimized through the YASARA structure minimization routine followed by FoldX RepairPDB .…”