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In Silico screening for functional candidates amongst hypothetical proteins.

ABSTRACT: BACKGROUND: The definition of a hypothetical protein is a protein that is predicted to be expressed from an open reading frame, but for which there is no experimental evidence of translation. Hypothetical proteins constitute a substantial fraction of proteomes of human as well as of other eukaryotes. With the general belief that the majority of hypothetical proteins are the product of pseudogenes, it is essential to have a tool with the ability of pinpointing the minority of hypothetical proteins with a high probability of being expressed. RESULTS: Here, we present an in silico selection strategy where eukaryotic hypothetical proteins are sorted according to two criteria that can be reliably identified in silico: the presence of subcellular targeting signals and presence of characterized protein domains. To validate the selection strategy we applied it on a database of human hypothetical proteins dating to 2006 and compared the proteins predicted to be expressed by our selecting strategy, with their status in 2008. For the comparison we focused on mitochondrial proteins, since considerable amounts of research have focused on this field in between 2006 and 2008. Therefore, many proteins, defined as hypothetical in 2006, have later been characterized as mitochondrial. CONCLUSION: Among the total amount of human proteins hypothetical in 2006, 21% have later been experimentally characterized and 6% of those have been shown to have a role in a mitochondrial context. In contrast, among the selected hypothetical proteins from the 2006 dataset, predicted by our strategy to have a mitochondrial role, 53-62% have later been experimentally characterized, and 85% of these have actually been assigned a role in mitochondria by 2008.Therefore our in silico selection strategy can be used to select the most promising candidates for subsequent in vitro and in vivo analyses.

SUBMITTER: Desler C

PROVIDER: S-EPMC2758874 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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In Silico screening for functional candidates amongst hypothetical proteins.

Desler Claus C Suravajhala Prashanth P Sanderhoff May M Rasmussen Merete M Rasmussen Lene Juel LJ

BMC bioinformatics 20090916

<h4>Background</h4>The definition of a hypothetical protein is a protein that is predicted to be expressed from an open reading frame, but for which there is no experimental evidence of translation. Hypothetical proteins constitute a substantial fraction of proteomes of human as well as of other eukaryotes. With the general belief that the majority of hypothetical proteins are the product of pseudogenes, it is essential to have a tool with the ability of pinpointing the minority of hypothetical ...[more]

PMID: 19754976

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Project description:Plasmodium falciparum is one of the plasmodium species responsible for the majority of life-threatening malaria cases. The current antimalarial therapies are becoming less effective due to growing drug resistance, leading to the urgent requirement for alternative and more effective antimalarial drugs or vaccines. To facilitate the novel drug discovery or vaccine development efforts, recent advances in sequencing technologies provide valuable information about the whole genome of the parasite, yet a lot more needs to be deciphered due to its incomplete proteome annotation. Surprisingly, out of the 5,389 proteins currently annotated in the Plasmodium falciparum 3D7 strain, 1,626 proteins (∼30% data) are annotated as hypothetical proteins. In parasite genomic studies, the challenge to annotate hypothetical proteins is often ignored, which may obscure the crucial information related to the pathogenicity of the parasite. In this study, we attempt to characterize hypothetical proteins of the parasite to identify novel drug targets using a computational pipeline. The study reveals that out of the overall pool of the hypothetical proteins, 266 proteins have conserved functional signatures. Furthermore, the pathway analysis of these proteins revealed that 23 proteins have an essential role in various biochemical, signalling and metabolic pathways. Additionally, all the proteins (266) were subjected to computational structure analysis. We could successfully model 11 proteins. We validated and checked the structural stability of the models by performing molecular dynamics simulation. Interestingly, eight proteins show stable conformations, and seven proteins are specific for Plasmodium falciparum, based on homology analysis. Lastly, mapping the seven shortlisted hypothetical proteins on the Plasmodium falciparum protein-protein interaction network revealed 3,299 nodes and 2,750,692 edges. Our study revealed interesting functional details of seven hypothetical proteins of the parasite, which help learn more about the less-studied molecules and their interactions, providing valuable clues to unravel the role of these proteins via future experimental validation.

Project description:BackgroundMonkeypox virus is a small, double-stranded DNA virus that causes a zoonotic disease called Monkeypox. The disease has spread from Central and West Africa to Europe and North America and created havoc in some countries all around the world. The complete genome of the Monkeypox virus Zaire-96-I-16 has been sequenced. The viral strain contains 191 protein-coding genes with 30 hypothetical proteins whose structure and function are still unknown. Hence, it is imperative to functionally and structurally annotate the hypothetical proteins to get a clear understanding of novel drug and vaccine targets. The purpose of the study was to characterize the 30 hypothetical proteins through the determination of physicochemical properties, subcellular characterization, function prediction, functional domain prediction, structure prediction, structure validation, structural analysis, and ligand binding sites using Bioinformatics tools.ResultsThe structural and functional analysis of 30 hypothetical proteins was carried out in this research. Out of these, 3 hypothetical functions (Q8V547, Q8V4S4, Q8V4Q4) could be assigned a structure and function confidently. Q8V547 protein in Monkeypox virus Zaire-96-I-16 is predicted as an apoptosis regulator which promotes viral replication in the infected host cell. Q8V4S4 is predicted as a nuclease responsible for viral evasion in the host. The function of Q8V4Q4 is to prevent host NF-kappa-B activation in response to pro-inflammatory cytokines like TNF alpha or interleukin 1 beta.ConclusionsOut of the 30 hypothetical proteins of Monkeypox virus Zaire-96-I-16, 3 were annotated using various bioinformatics tools. These proteins function as apoptosis regulators, nuclease, and inhibitors of NF-Kappa-B activator. The functional and structural annotation of the proteins can be used to perform a docking with potential leads to discover novel drugs and vaccines against the Monkeypox. In vivo research can be carried out to identify the complete potential of the annotated proteins.

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In Silico screening for functional candidates amongst hypothetical proteins.

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In Silico screening for functional candidates amongst hypothetical proteins.

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