May
20
2015
0

New CABS-dock method enables protein-peptide docking without prior knowledge of the binding site

By Sebastian Kmiecik, Researcher at the Laboratory of Theory of Biopolymers, University of Warsaw

Researchers from the Laboratory of Theory of Biopolymers at the University of Warsaw have developed CABS-dock, a new computational method (available as a web server) which allows predicting the structure of protein-peptide complexes and uses no knowledge about the peptide binding site nor the peptide conformation. The method utilizes highly efficient simulation approach for molecular docking of peptides to proteins.

Protein-peptide interactions play a key role in cell functions. Their structural characterization, though challenging, is important for the discovery of new drugs. The CABS-dock web server provides an interface for modeling protein-peptide interactions using a highly efficient protocol for the flexible docking of peptides to proteins. While other docking algorithms (like Rosetta FlexPepDock or HADDOCK) require pre-defined localization of the binding site, CABS-dock doesn’t require such knowledge. Given a protein receptor structure and a peptide sequence (and starting from random conformations and positions of the peptide), CABS-dock performs simulation search for the binding site allowing for full flexibility of the peptide and small fluctuations of the receptor backbone. This protocol was extensively tested over the largest dataset of non-redundant protein-peptide interactions available to date (including bound and unbound docking cases). For over 80% of bound and unbound dataset cases, high or medium accuracy models were obtained (sufficient for practical applications). The performance summary is presented in the Figure below.

image001

 

 

Figure caption. CABS-dock performance summary for 103 bound and 68 unbound benchmark cases. The percentages of high-, medium- or low-accuracy models (high accuracy: rmsd<3 Å; medium accuracy: 3 Å ≤ rmsd ≤ 5.5 Å; low accuracy: rmsd > 5.5 Å) are reported for the best quality models found in the sets of 10 000 models (all) and in the sets of 10 final models (top 10). Figure is taken from the CABS-dock paper [Nucleic Acids Res, 2015, doi: 10.1093/nar/gkv456]. Entire benchmark results are available in the online CABS-dock materials at http://biocomp.chem.uw.edu.pl/CABSdock/benchmark

Additionally, as optional features, CABS-dock enables to exclude user-selected binding modes from docking search or to increase the level of flexibility for chosen receptor fragments. CABS-dock is freely available as a web server at http://biocomp.chem.uw.edu.pl/CABSdock

Article: Mateusz Kurcinski, Michal Jamroz, Maciej Blaszczyk, Andrzej Kolinski, Sebastian Kmiecik, CABS-dock web server for flexible docking of peptides to proteins without prior knowledge of the binding site, Nucleic Acids Research, 2015. doi: 10.1093/nar/gkv456

Supplementary video: http://www.youtube.com/watch?v=EOqRF-JOTFg

CABS-dock

Video description: An example simulation of protein-peptide molecular docking using CABS-dock web server. In the movie, the assembly of major histocompatibility complex (MHC)-peptide structure is simulated. Experimental peptide structure is shown in green, while the simulated peptide in red. The movie shows 1 of 10 trajectories generated in a standard CABS-dock simulation run. The predicted peptide structure, shown at the simulation end, differs from the experimental structure by 1.8 Ångstroms.

Mar
21
2014
1

Poly-publications on the polypharmacology of kinase/bromodomains dual inhibitors

When you consider how vast the chemical space is and how restricted the topology and chemical environment of a specific pocket in a protein is, it’s quite surprising we can find molecules that the protein was not evolved to bind that can nonetheless bind and inhibit it potently. It is therefore even more surprising when a single molecule can potently hit two completely unrelated (by sequence, by structure and by function) proteins. Thus, when two independent groups publish such dual kinase/bromodomain inhibitors a week a part from each other, the mind reels.

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Feb
20
2014
0
Jun
19
2012
2

Direct and selective small molecule activation of BAX

A virtual docking screen discovers a small molecule activator of the pro-apoptotic protein BAX. This novel approach could lead to a ‘new generation’ of apoptotic modulators that directly activate BCL-2 killer proteins. Moreover – it’s cool!

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Apr
26
2012
0

Weekly literature review

A selection of this week’s interesting papers, brought to you via the Furman Lab

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Written by admin in: Literature Reviews,Title Madness |
Apr
16
2012
0

Weekly literature review

A selection of this week’s interesting papers, brought to you via the Furman Lab

(more…)

Apr
05
2012
0

Weekly literature review

A selection of this week’s interesting papers, brought to you via the Furman Lab

(more…)

Written by admin in: Literature Reviews,Title Madness | Tags:
Apr
03
2012
0

Protein–protein interaction inhibitors get into the groove

In a recent ‘News and Analysis’ piece on Nature Reviews Drug Discovery,  Asher Mullard, heralds the advancement in drug discovery efforts against Protein-protein interactions – “the unmined biology gold reserve”.

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Mar
14
2012
0

Tezcan-RDG supramolecular design collab in the news

Stu Borman wrote a nice piece in Chemical & Engineering News (CEN) highlighting a recent paper in Nature Chemistry that presents the work of a collaboration between the Tezcan Lab at UCSD and the Rosetta Design Group. In this work, a monomeric protein was redesigned to become capable of forming metal and pH tunable nano- to micro- scale sheets, tubes, and other assemblies.


Mr. McGuire: I just want to say one word to you. Just one word.

Benjamin: Yes, sir.

Mr. McGuire: Are you listening?

Benjamin: Yes, I am.

Mr. McGuire: Plastics. Proteins.

Benjamin: Exactly how do you mean?

Written by Xavier Ambroggio in: Literature Reviews | Tags: , , , ,
Nov
05
2011
0

A twitter roundup

For those not yet following us (@molmodelblog) on twitter, a roundup of interesting links from the weekend:

Written by admin in: Resources,Title Madness | Tags: ,

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