Protein models: the Grand Challenge of protein docking (original) (raw)

Protein models docking benchmark 2

Proteins, 2015

Structural characterization of protein-protein interactions is essential for our ability to understand life processes. However, only a fraction of known proteins have experimentally determined structures. Such structures provide templates for modeling of a large part of the proteome, where individual proteins can be docked by template-free or template-based techniques. Still, the sensitivity of the docking methods to the inherent inaccuracies of protein models, as opposed to the experimentally determined high-resolution structures, remains largely untested, primarily due to the absence of appropriate benchmark set(s). Structures in such a set should have predefined inaccuracy levels and, at the same time, resemble actual protein models in terms of structural motifs/packing. The set should also be large enough to ensure statistical reliability of the benchmarking results. We present a major update of the previously developed benchmark set of protein models. For each interactor, six m...

High-resolution protein–protein docking

Current Opinion in Structural Biology, 2006

The high-resolution prediction of protein-protein docking can now create structures with atomic-level accuracy. This progress arises from both improvements in the rapid sampling of conformations and increased accuracy of binding free energy calculations. Consequently, the quality of models submitted to the blind prediction challenge CAPRI (Critical Assessment of PRedicted Interactions) has steadily increased, including complexes predicted from homology structures of one binding partner and complexes with atomic accuracy at the interface. By exploiting experimental information, docking has created model structures for real applications, even when confronted with challenges such as moving backbones and uncertain monomer structures. Work remains to be done in docking large or flexible proteins, ranking models consistently, and producing models accurate enough to allow computational design of higher affinities or specificities.

Protein Docking by the Interface Structure Similarity: How Much Structure Is Needed?

2011

The increasing availability of co-crystallized protein-protein complexes provides an opportunity to use template-based modeling for protein-protein docking. Structure alignment techniques are useful in detection of remote target-template similarities. The size of the structure involved in the alignment is important for the success in modeling. This paper describes a systematic large-scale study to find the optimal definition/size of the interfaces for the structure alignment-based docking applications. The results showed that structural areas corresponding to the cutoff values,12 A ˚ across the interface inadequately represent structural details of the interfaces. With the increase of the cutoff beyond 12 A˚, the success rate for the benchmark set of 99 protein complexes, did not increase significantly for higher accuracy models, and decreased for lower-accuracy models. The 12 A ˚ cutoff was optimal in our interface alignment-based docking, and a likely best choice for the large-sca...

Protein-protein docking dealing with the unknown

Journal of Computational Chemistry, 2009

Protein-protein binding is one of the critical events in biology, and knowledge of proteic complexes three-dimensional structures is of fundamental importance for the biochemical study of pharmacologic compounds. In the past two decades there was an emergence of a large variety of algorithms designed to predict the structures of protein-protein complexes-a procedure named docking. Computational methods, if accurate and reliable, could play an important role, both to infer functional properties and to guide new experiments. Despite the outstanding progress of the methodologies developed in this area, a few problems still prevent protein-protein docking to be a widespread practice in the structural study of proteins. In this review we focus our attention on the principles that govern docking, namely the algorithms used for searching and scoring, which are usually referred as the docking problem. We also focus our attention on the use of a flexible description of the proteins under study and the use of biological information as the localization of the hot spots, the important residues for protein-protein binding. The most common docking softwares are described too.

LightDock: a new multi-scale approach to protein–protein docking

Bioinformatics, 2017

Motivation: Computational prediction of protein-protein complex structure by docking can provide structural and mechanistic insights for protein interactions of biomedical interest. However, current methods struggle with difficult cases, such as those involving flexible proteins, low-affinity complexes or transient interactions. A major challenge is how to efficiently sample the structural and energetic landscape of the association at different resolution levels, given that each scoring function is often highly coupled to a specific type of search method. Thus, new methodologies capable of accommodating multi-scale conformational flexibility and scoring are strongly needed. Results: We describe here a new multi-scale protein-protein docking methodology, LightDock, capable of accommodating conformational flexibility and a variety of scoring functions at different resolution levels. Implicit use of normal modes during the search and atomic/coarse-grained combined scoring functions yielded improved predictive results with respect to state-of-the-art rigidbody docking, especially in flexible cases. Availability and implementation: The source code of the software and installation instructions are available for download at https://life.bsc.es/pid/lightdock/.

Towards the prediction of protein interaction partners using physical docking

Molecular Systems Biology, 2011

Deciphering the whole network of protein interactions for a given proteome ('interactome') is the goal of many experimental and computational efforts in Systems Biology. Separately the prediction of the structure of protein complexes by docking methods is a well-established scientific area. To date, docking programs have not been used to predict interaction partners. We provide a proof of principle for such an approach. Using a set of protein complexes representing known interactors in their unbound form, we show that a standard docking program can distinguish the true interactors from a background of 922 non-redundant potential interactors. We additionally show that true interactions can be distinguished from non-likely interacting proteins within the same structural family. Our approach may be put in the context of the proposed 'funnel-energy model'; the docking algorithm may not find the native complex, but it distinguishes binding partners because of the higher probability of favourable models compared with a collection of non-binders. The potential exists to develop this proof of principle into new approaches for predicting interaction partners and reconstructing biological networks.

Structural templates for comparative protein docking

Proteins, 2014

Structural characterization of protein-protein interactions is important for understanding life processes. Because of the inherent limitations of experimental techniques, such characterization requires computational approaches. Along with the traditional protein-protein docking (free search for a match between two proteins), comparative (template-based) modeling of protein-protein complexes has been gaining popularity. Its development puts an emphasis on full and partial structural similarity between the target protein monomers and the protein-protein complexes previously determined by experimental techniques (templates). The template-based docking relies on the quality and diversity of the template set. We present a carefully curated, non-redundant library of templates containing 4,950 full structures of binary complexes and 5,936 protein-protein interfaces extracted from the full structures at 12Å distance cut-off. Redundancy in the libraries was removed by clustering the PDB stru...

Accounting for conformational changes during protein–protein docking

Current Opinion in Structural Biology, 2010

Three-dimensional structures of only a small fraction of known protein-protein complexes are currently known. Meanwhile, computational methods are of increasing importance to provide structural models for known protein-protein interactions. Current protein-protein docking methods are often successful if experimentally determined partner proteins undergo little conformational changes upon binding. However, the realistic and computationally efficient treatment of conformational changes especially of the protein backbone during docking remains a challenge. New promising approaches of flexible refinement, ensemble docking and explicit inclusion of flexibility during the entire docking process have been developed. A significant fraction of known proteinprotein interactions can be modeled based on homology to known protein-protein complexes which in many cases also requires efficient flexible refinement to provide accurate structural models.

HADDOCK: a protein-protein docking approach based on biochemical or biophysical data

2000

The structure determination,of protein-protein complexes,is a rather tedious and lengthy process, by both NMR and X-ray crystallography. Several methods based on docking to study protein complexes,have also been well developed,over the past few years. Most of these approaches are not driven by experimental,data but are based on a,combination,of energetics and shape complementarity. Here we present,an approach,called HADDOCK (High Ambiguity