Parallel‐ProBiS: Fast parallel algorithm for local structural comparison of protein structures and binding sites

Konc, Janez; Depolli, Matjaž; Trobec, Roman; Rozman, Kati; Janežič, Dušanka

doi:10.1002/jcc.23048

Cited by 15 publications

(12 citation statements)

References 18 publications

(28 reference statements)

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“…In the binding site network, nodes are binding site structures and similar sites are connected by edges. Figure 1 presents the workflow in a sequence of 5 steps: 1) we generated the non-redundant protein structure databases using sequence identity cutoffs of 40, 70, and 90%; 2) non-redundant binding site structures were extracted from the databases; 3) structural similarities between all binding sites were calculated using the ProBiS 2 , 3 ; 4) the similarity scores were normalized into z-scores and the pairs of binding site pairs whose z-score is higher than a pre-defined threshold were connected by edges and 5) structurally similar binding sites were classified into communities to reduce the complexity of the network. Using the identified binding site communities, we investigated their size distribution, functional enrichment, and their relationships with ligands and domain structures.…”

Section: Resultsmentioning

confidence: 99%

Global organization of a binding site network gives insight into evolution and structure-function relationships of proteins

Lee

Konc

Janežič

et al. 2017

Sci Rep

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The global organization of protein binding sites is analyzed by constructing a weighted network of binding sites based on their structural similarities and detecting communities of structurally similar binding sites based on the minimum description length principle. The analysis reveals that there are two central binding site communities that play the roles of the network hubs of smaller peripheral communities. The sizes of communities follow a power-law distribution, which indicates that the binding sites included in larger communities may be older and have been evolutionary structural scaffolds of more recent ones. Structurally similar binding sites in the same community bind to diverse ligands promiscuously and they are also embedded in diverse domain structures. Understanding the general principles of binding site interplay will pave the way for improved drug design and protein design.

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Section: Resultsmentioning

confidence: 99%

Global organization of a binding site network gives insight into evolution and structure-function relationships of proteins

Lee

Konc

Janežič

et al. 2017

Sci Rep

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“…Binding sites were predicted using the ProBiS web server [17] at http://probis.cmm.ki.si . Comparisons of binding site structures were done using the parallel ProBiS program [33] (version 2.4.2) freely available at http://probis.cmm.ki.si/?what=parallel . MD simulations were carried out on the clusters of personal computers (CROW) at the National Institute of Chemistry in Ljubljana [34] , using the CHARMM biomolecular simulation program [35] and CHARMMing web server [36] .…”

Section: Methodsmentioning

confidence: 99%

Structure-Based Function Prediction of Uncharacterized Protein Using Binding Sites Comparison

et al. 2013

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A challenge in structural genomics is prediction of the function of uncharacterized proteins. When proteins cannot be related to other proteins of known activity, identification of function based on sequence or structural homology is impossible and in such cases it would be useful to assess structurally conserved binding sites in connection with the protein's function. In this paper, we propose the function of a protein of unknown activity, the Tm1631 protein from Thermotoga maritima, by comparing its predicted binding site to a library containing thousands of candidate structures. The comparison revealed numerous similarities with nucleotide binding sites including specifically, a DNA-binding site of endonuclease IV. We constructed a model of this Tm1631 protein with a DNA-ligand from the newly found similar binding site using ProBiS, and validated this model by molecular dynamics. The interactions predicted by the Tm1631-DNA model corresponded to those known to be important in endonuclease IV-DNA complex model and the corresponding binding free energies, calculated from these models were in close agreement. We thus propose that Tm1631 is a DNA binding enzyme with endonuclease activity that recognizes DNA lesions in which at least two consecutive nucleotides are unpaired. Our approach is general, and can be applied to any protein of unknown function. It might also be useful to guide experimental determination of function of uncharacterized proteins.

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“…An open source of parallel-ProBiS 26 (version 2.3.8) was taken from the ProBiS web site (http://probis.cmm.ki.si) 27 All BS-structures for the benchmark set and the structure library were converted into the surface format (.srf) files for the template ligand search using ProBiS. Z_SCORE and SURF_VECTOR_ANGLE were set to −10.0 and 4.0, respectively, to turn off filtering of local structure alignment results.…”

Section: Methodsmentioning

confidence: 99%

Identification of Ligand Templates using Local Structure Alignment for Structure-Based Drug Design

Lee

2012

J. Chem. Inf. Model.

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With a rapid increase in the number of high-resolution protein-ligand structures, the known protein-ligand structures can be used to gain insight into ligand-binding modes in a target protein. Based on the fact that the structurally similar binding sites share information about their ligands, we have developed a local structure alignment tool, G-LoSA (Graph-based Local Structure Alignment). In G-LoSA, the known protein-ligand binding-site structure library is searched to detect binding-site structures with similar geometry and physicochemical properties to a query binding-site structure regardless of sequence continuity and protein fold. Then, the ligands in the identified complexes are used as templates (i.e., template ligands) to predict/design a ligand for the target protein. The performance of G-LoSA is validated against 76 benchmark targets from the Astex diverse set. Using the currently available protein-ligand structure library, G-LoSA is able to identify a single template ligand (from a non-homologous protein complex) that is highly similar to the target ligand in more than half of the benchmark targets. In addition, our benchmark analyses show that an assembly of structural fragments from multiple template ligands with partial similarity to the target ligand can be used to design novel ligand structures specific to the target protein. This study clearly indicates that a template-based ligand modeling has potential for de novo ligand design and can be a complementary approach to the receptor structure based methods.

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Parallel‐ProBiS: Fast parallel algorithm for local structural comparison of protein structures and binding sites

Cited by 15 publications

References 18 publications

Global organization of a binding site network gives insight into evolution and structure-function relationships of proteins

Global organization of a binding site network gives insight into evolution and structure-function relationships of proteins

Structure-Based Function Prediction of Uncharacterized Protein Using Binding Sites Comparison

Identification of Ligand Templates using Local Structure Alignment for Structure-Based Drug Design

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