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In
molecular biology Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...
, an interactome is the whole set of molecular interactions in a particular
cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
. The term specifically refers to physical interactions among molecules (such as those among proteins, also known as
protein–protein interaction Protein–protein interactions (PPIs) are physical contacts of high specificity established between two or more protein molecules as a result of biochemical events steered by interactions that include electrostatic forces, hydrogen bonding and th ...
s, PPIs; or between small molecules and proteins) but can also describe sets of indirect interactions among genes (
genetic interactions Epistasis is a phenomenon in genetics in which the effect of a gene mutation is dependent on the presence or absence of mutations in one or more other genes, respectively termed modifier genes. In other words, the effect of the mutation is dep ...
). The word "interactome" was originally coined in 1999 by a group of French scientists headed by Bernard Jacq. Mathematically, interactomes are generally displayed as
graphs Graph may refer to: Mathematics *Graph (discrete mathematics), a structure made of vertices and edges **Graph theory, the study of such graphs and their properties *Graph (topology), a topological space resembling a graph in the sense of discre ...
. Though interactomes may be described as
biological network A biological network is a method of representing systems as complex sets of binary interactions or relations between various biological entities. In general, networks or graphs are used to capture relationships between entities or objects. A typi ...
s, they should not be confused with other networks such as
neural network A neural network is a network or circuit of biological neurons, or, in a modern sense, an artificial neural network, composed of artificial neurons or nodes. Thus, a neural network is either a biological neural network, made up of biological ...
s or
food web A food web is the natural interconnection of food chains and a graphical representation of what-eats-what in an ecological community. Another name for food web is consumer-resource system. Ecologists can broadly lump all life forms into one ...
s.


Molecular interaction networks

Molecular interactions can occur between molecules belonging to different biochemical families (proteins, nucleic acids, lipids, carbohydrates, etc.) and also within a given family. Whenever such molecules are connected by physical interactions, they form molecular interaction networks that are generally classified by the nature of the compounds involved. Most commonly, ''interactome'' refers to ''
protein–protein interaction Protein–protein interactions (PPIs) are physical contacts of high specificity established between two or more protein molecules as a result of biochemical events steered by interactions that include electrostatic forces, hydrogen bonding and th ...
'' (PPI) network (PIN) or subsets thereof. For instance, the Sirt-1 protein interactome and Sirt family second order interactome is the network involving Sirt-1 and its directly interacting proteins where as second order interactome illustrates interactions up to second order of neighbors (Neighbors of neighbors). Another extensively studied type of interactome is the protein–DNA interactome, also called a ''gene-regulatory network'', a network formed by transcription factors, chromatin regulatory proteins, and their target genes. Even ''
metabolic network A metabolic network is the complete set of metabolic and physical processes that determine the physiological and biochemical properties of a cell. As such, these networks comprise the chemical reactions of metabolism, the metabolic pathways, as w ...
s'' can be considered as molecular interaction networks: metabolites, i.e. chemical compounds in a cell, are converted into each other by
enzymes Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
, which have to bind their substrates physically. In fact, all interactome types are interconnected. For instance, protein interactomes contain many enzymes which in turn form biochemical networks. Similarly, gene regulatory networks overlap substantially with protein interaction networks and signaling networks.


Size

It has been suggested that the size of an organism's interactome correlates better than
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
size with the biological complexity of the organism. Although protein–protein interaction maps containing several thousand binary interactions are now available for several species, none of them is presently complete and the size of interactomes is still a matter of debate.


Yeast

The yeast interactome, i.e. all protein–protein interactions among proteins of ''
Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...
'', has been estimated to contain between 10,000 and 30,000 interactions. A reasonable estimate may be on the order of 20,000 interactions. Larger estimates often include indirect or predicted interactions, often from
affinity purification Affinity chromatography is a method of separating a biomolecule from a mixture, based on a highly specific molecular binding, macromolecular binding interaction between the biomolecule and another substance. The specific type of binding interacti ...
/
mass spectrometry Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a ''mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is use ...
(AP/MS) studies.


Genetic interaction networks

Genes interact in the sense that they affect each other's function. For instance, a
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
may be harmless, but when it is combined with another mutation, the combination may turn out to be lethal. Such genes are said to "interact genetically". Genes that are connected in such a way form ''genetic interaction networks''. Some of the goals of these networks are: develop a functional map of a cell's processes, drug target identification using
chemoproteomics Chemoproteomics entails a broad array of techniques used to identify and interrogate protein- small molecule interactions. Chemoproteomics complements phenotypic drug discovery, a paradigm that aims to discover lead compounds on the basis of allev ...
, and to predict the function of uncharacterized genes. In 2010, the most "complete" gene interactome produced to date was compiled from about 5.4 million two-gene comparisons to describe "the interaction profiles for ~75% of all genes in the
budding yeast ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...
", with ~170,000 gene interactions. The genes were grouped based on similar function so as to build a functional map of the cell's processes. Using this method the study was able to predict known gene functions better than any other genome-scale data set as well as adding functional information for genes that hadn't been previously described. From this model genetic interactions can be observed at multiple scales which will assist in the study of concepts such as gene conservation. Some of the observations made from this study are that there were twice as many negative as positive interactions, negative interactions were more informative than positive interactions, and genes with more connections were more likely to result in lethality when disrupted.


Interactomics

Interactomics is a discipline at the intersection of
bioinformatics Bioinformatics () is an interdisciplinary field that develops methods and software tools for understanding biological data, in particular when the data sets are large and complex. As an interdisciplinary field of science, bioinformatics combi ...
and
biology Biology is the scientific study of life. It is a natural science with a broad scope but has several unifying themes that tie it together as a single, coherent field. For instance, all organisms are made up of cells that process hereditary i ...
that deals with studying both the interactions and the consequences of those interactions between and among
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s, and other molecules within a
cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
. Interactomics thus aims to compare such networks of interactions (i.e., interactomes) between and within species in order to find how the traits of such networks are either preserved or varied. Interactomics is an example of "top-down" systems biology, which takes an overhead view of a biosystem or organism. Large sets of genome-wide and proteomic data are collected, and correlations between different molecules are inferred. From the data new hypotheses are formulated about feedbacks between these molecules. These hypotheses can then be tested by new experiments.


Experimental methods to map interactomes

The study of interactomes is called interactomics. The basic unit of a protein network is the protein–protein interaction (PPI). While there are numerous methods to study PPIs, there are relatively few that have been used on a large scale to map whole interactomes. The
yeast two hybrid Two-hybrid screening (originally known as yeast two-hybrid system or Y2H) is a molecular biology technique used to discover protein–protein interactions (PPIs) and protein–DNA interactions by testing for physical interactions (such as bindi ...
system (Y2H) is suited to explore the binary interactions among two proteins at a time. Affinity purification and subsequent mass spectrometry is suited to identify a protein complex. Both methods can be used in a high-throughput (HTP) fashion. Yeast two hybrid screens allow false positive interactions between proteins that are never expressed in the same time and place; affinity capture mass spectrometry does not have this drawback, and is the current gold standard. Yeast two-hybrid data better indicates non-specific tendencies towards sticky interactions rather while affinity capture mass spectrometry better indicates functional in vivo protein–protein interactions.


Computational methods to study interactomes

Once an interactome has been created, there are numerous ways to analyze its properties. However, there are two important goals of such analyses. First, scientists try to elucidate the systems properties of interactomes, e.g. the topology of its interactions. Second, studies may focus on individual proteins and their role in the network. Such analyses are mainly carried out using
bioinformatics Bioinformatics () is an interdisciplinary field that develops methods and software tools for understanding biological data, in particular when the data sets are large and complex. As an interdisciplinary field of science, bioinformatics combi ...
methods and include the following, among many others:


Validation

First, the coverage and quality of an interactome has to be evaluated. Interactomes are never complete, given the limitations of experimental methods. For instance, it has been estimated that typical
Y2H Two-hybrid screening (originally known as yeast two-hybrid system or Y2H) is a molecular biology technique used to discover protein–protein interactions (PPIs) and protein–DNA interactions by testing for physical interactions (such as bindi ...
screens detect only 25% or so of all interactions in an interactome. The coverage of an interactome can be assessed by comparing it to benchmarks of well-known interactions that have been found and validated by independent assays. Other methods filter out false positives calculating the similarity of known annotations of the proteins involved or define a likelihood of interaction using the subcellular localization of these proteins.


Predicting PPIs

Using experimental data as a starting point, ''homology transfer'' is one way to predict interactomes. Here, PPIs from one organism are used to predict interactions among homologous proteins in another organism ("''interologs''"). However, this approach has certain limitations, primarily because the source data may not be reliable (e.g. contain false positives and false negatives). In addition, proteins and their interactions change during evolution and thus may have been lost or gained. Nevertheless, numerous interactomes have been predicted, e.g. that of ''
Bacillus licheniformis ''Bacillus licheniformis'' is a bacterium commonly found in the soil. It is found on bird feathers, especially chest and back plumage, and most often in ground-dwelling birds (like sparrows) and aquatic species (like ducks). It is a gram-posit ...
''. Some algorithms use experimental evidence on structural complexes, the atomic details of binding interfaces and produce detailed atomic models of protein–protein complexes as well as other protein–molecule interactions. Other algorithms use only sequence information, thereby creating unbiased complete networks of interaction with many mistakes. Some methods use machine learning to distinguish how interacting protein pairs differ from non-interacting protein pairs in terms of pairwise features such as cellular colocalization, gene co-expression, how closely located on a DNA are the genes that encode the two proteins, and so on.
Random Forest Random forests or random decision forests is an ensemble learning method for classification, regression and other tasks that operates by constructing a multitude of decision trees at training time. For classification tasks, the output of th ...
has been found to be most-effective machine learning method for protein interaction prediction. Such methods have been applied for discovering protein interactions on human interactome, specifically the interactome of
Membrane proteins Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...
and the interactome of Schizophrenia-associated proteins.


Text mining of PPIs

Some efforts have been made to extract systematically interaction networks directly from the scientific literature. Such approaches range in terms of complexity from simple co-occurrence statistics of entities that are mentioned together in the same context (e.g. sentence) to sophisticated natural language processing and machine learning methods for detecting interaction relationships.


Protein function prediction

Protein interaction networks have been used to predict the function of proteins of unknown functions. This is usually based on the assumption that uncharacterized proteins have similar functions as their interacting proteins (''guilt by association''). For example, YbeB, a protein of unknown function was found to interact with ribosomal proteins and later shown to be involved in bacterial and eukaryotic (but not archaeal)
translation Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...
. Although such predictions may be based on single interactions, usually several interactions are found. Thus, the whole network of interactions can be used to predict protein functions, given that certain functions are usually enriched among the interactors. The term ''hypothome'' has been used to denote an interactome wherein at least one of the genes or proteins is a hypothetical protein.


Perturbations and disease

The ''
topology In mathematics, topology (from the Greek language, Greek words , and ) is concerned with the properties of a mathematical object, geometric object that are preserved under Continuous function, continuous Deformation theory, deformations, such ...
'' of an interactome makes certain predictions how a network reacts to the perturbation (e.g. removal) of nodes (proteins) or edges (interactions). Such perturbations can be caused by
mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
of genes, and thus their proteins, and a network reaction can manifest as a
disease A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...
. A network analysis can identify
drug target A biological target is anything within a living organism to which some other entity (like an endogenous ligand (biochemistry), ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes ...
s and
biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
s of diseases.


Network structure and topology

Interaction networks can be analyzed using the tools of
graph theory In mathematics, graph theory is the study of ''graphs'', which are mathematical structures used to model pairwise relations between objects. A graph in this context is made up of '' vertices'' (also called ''nodes'' or ''points'') which are conne ...
. Network properties include the
degree Degree may refer to: As a unit of measurement * Degree (angle), a unit of angle measurement ** Degree of geographical latitude ** Degree of geographical longitude * Degree symbol (°), a notation used in science, engineering, and mathematics ...
distribution,
clustering coefficient In graph theory, a clustering coefficient is a measure of the degree to which nodes in a graph tend to cluster together. Evidence suggests that in most real-world networks, and in particular social networks, nodes tend to create tightly knit groups ...
s,
betweenness centrality In graph theory, betweenness centrality (or "betweeness centrality") is a measure of centrality in a graph based on shortest paths. For every pair of vertices in a connected graph, there exists at least one shortest path between the vertices such ...
, and many others. The distribution of properties among the proteins of an interactome has revealed that the interactome networks often have scale-free topology where functional modules within a network indicate specialized subnetworks. Such modules can be functional, as in a
signaling pathway In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
, or structural, as in a protein complex. In fact, it is a formidable task to identify protein complexes in an interactome, given that a network on its own does not directly reveal the presence of a stable complex.


Studied interactomes


Viral interactomes

Viral protein interactomes consist of interactions among viral or phage proteins. They were among the first interactome projects as their genomes are small and all proteins can be analyzed with limited resources. Viral interactomes are connected to their host interactomes, forming virus-host interaction networks. Some published virus interactomes include Bacteriophage * ''
Escherichia coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
''
bacteriophage lambda ''Enterobacteria phage λ'' (lambda phage, coliphage λ, officially ''Escherichia virus Lambda'') is a bacterial virus, or bacteriophage, that infects the bacterial species ''Escherichia coli'' (''E. coli''). It was discovered by Esther Lederb ...
* ''
Escherichia coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
'' bacteriophage T7 * ''
Streptococcus pneumoniae ''Streptococcus pneumoniae'', or pneumococcus, is a Gram-positive, spherical bacteria, alpha-hemolytic (under aerobic conditions) or beta-hemolytic (under anaerobic conditions), aerotolerant anaerobic member of the genus Streptococcus. They are ...
'' bacteriophage Dp-1 * ''
Streptococcus pneumoniae ''Streptococcus pneumoniae'', or pneumococcus, is a Gram-positive, spherical bacteria, alpha-hemolytic (under aerobic conditions) or beta-hemolytic (under anaerobic conditions), aerotolerant anaerobic member of the genus Streptococcus. They are ...
'' bacteriophage Cp-1 The lambda and VZV interactomes are not only relevant for the biology of these viruses but also for technical reasons: they were the first interactomes that were mapped with multiple
Y2H Two-hybrid screening (originally known as yeast two-hybrid system or Y2H) is a molecular biology technique used to discover protein–protein interactions (PPIs) and protein–DNA interactions by testing for physical interactions (such as bindi ...
vectors, proving an improved strategy to investigate interactomes more completely than previous attempts have shown. Human (mammalian) viruses * Human
varicella zoster virus Varicella-zoster virus (VZV), also known as human herpesvirus 3 (HHV-3, HHV3) or ''Human alphaherpesvirus 3'' (taxonomically), is one of nine known herpes viruses that can infect humans. It causes chickenpox (varicella) commonly affecting chil ...
(VZV) *
Chandipura virus ''Chandipura vesiculovirus'' (CHPV) is a member of the ''Rhabdoviridae'' family that is associated with an encephalitic illness in humans. It was first identified in 1965 after isolation from the blood of two patients from Chandipura village in ...
* Epstein-Barr virus (EBV) *
Hepatitis C virus The hepatitis C virus (HCV) is a small (55–65 nm in size), enveloped, positive-sense single-stranded RNA virus of the family ''Flaviviridae''. The hepatitis C virus is the cause of hepatitis C and some cancers such as liver cancer ( hepato ...
(HPC), Human-HCV interactions *
Hepatitis E virus The hepatitis E virus (HEV) is the causative agent of hepatitis E. It is of the species ''Orthohepevirus A.'' Globally, approximately 939 million corresponding to 1 in 8 individuals have ever experienced HEV infection. About 15–110 million ind ...
(HEV) *
Herpes simplex virus 1 Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names ''Human alphaherpesvirus 1'' and '' Human alphaherpesvirus 2'', are two members of the human ''Herpesviridae'' family, a set of viruses that produce viral inf ...
(HSV-1) *
Kaposi's sarcoma-associated herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is the ninth known human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses (ICTV) is ''Human gammaherpesvirus 8'', or HHV-8 in short. Like other herpesvirus ...
(KSHV) * Murine
cytomegalovirus ''Cytomegalovirus'' (''CMV'') (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order ''Herpesvirales'', in the family ''Herpesviridae'', in the subfamily ''Betaherpe ...
(mCMV)


Bacterial interactomes

Relatively few bacteria have been comprehensively studied for their protein–protein interactions. However, none of these interactomes are complete in the sense that they captured all interactions. In fact, it has been estimated that none of them covers more than 20% or 30% of all interactions, primarily because most of these studies have only employed a single method, all of which discover only a subset of interactions. Among the published bacterial interactomes (including partial ones) are The ''E. coli'' and ''Mycoplasma'' interactomes have been analyzed using large-scale protein complex affinity purification and mass spectrometry (AP/MS), hence it is not easily possible to infer direct interactions. The others have used extensive
yeast two-hybrid Two-hybrid screening (originally known as yeast two-hybrid system or Y2H) is a molecular biology technique used to discover protein–protein interactions (PPIs) and protein–DNA interactions by testing for physical interactions (such as bindi ...
(Y2H) screens. The ''Mycobacterium tuberculosis'' interactome has been analyzed using a bacterial two-hybrid screen (B2H). Note that numerous additional interactomes have been predicted using computational methods (see section above).


Eukaryotic interactomes

There have been several efforts to map eukaryotic interactomes through HTP methods. While no biological interactomes have been fully characterized, over 90% of proteins in ''Saccharomyces cerevisiae'' have been screened and their interactions characterized, making it the best-characterized interactome. Species whose interactomes have been studied in some detail include * ''
Schizosaccharomyces pombe ''Schizosaccharomyces pombe'', also called "fission yeast", is a species of yeast used in traditional brewing and as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically meas ...
'' * ''
Caenorhabditis elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (ro ...
'' * ''
Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly" or "pomace fly". Starting with Ch ...
'' * ''Homo sapiens'' Recently, the pathogen-host interactomes of Hepatitis C Virus/Human (2008), Epstein Barr virus/Human (2008), Influenza virus/Human (2009) were delineated through HTP to identify essential molecular components for pathogens and for their host's immune system.


Predicted interactomes

As described above, PPIs and thus whole interactomes can be predicted. While the reliability of these predictions is debatable, they are providing hypotheses that can be tested experimentally. Interactomes have been predicted for a number of species, e.g. * Human (''
Homo sapiens Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
'') * Rice (''
Oryza sativa ''Oryza sativa'', commonly known as Asian rice or indica rice, is the plant species most commonly referred to in English as ''rice''. It is the type of farmed rice whose cultivars are most common globally, and was first domesticated in the Yan ...
'') * ''
Xanthomonas oryzae ''Xanthomonas oryzae'' is a species of bacteria. The major host of the bacterium is rice. The species contains two pathovars, neither of which is native to Europe: ''X. o.'' pv. ''oryzae'' and ''X. o.'' pv. ''oryzicola''. ''Xanthomonas oryzae ...
'' * ''
Arabidopsis thaliana ''Arabidopsis thaliana'', the thale cress, mouse-ear cress or arabidopsis, is a small flowering plant native to Eurasia and Africa. ''A. thaliana'' is considered a weed; it is found along the shoulders of roads and in disturbed land. A winter a ...
'' * Tomato (''
Solanum lycopersicum The tomato is the edible berry of the plant ''Solanum lycopersicum'', commonly known as the tomato plant. The species originated in western South America, Mexico, and Central America. The Mexican Nahuatl word gave rise to the Spanish word ...
'') * Field mustard (''
Brassica rapa ''Brassica rapa'' is a plant species growing in various widely cultivated forms including the turnip (a root vegetable); napa cabbage, bomdong, bok choy, and rapini. ''Brassica rapa'' subsp. ''oleifera'' is an oilseed which has many common n ...
'') * ''Maize, corn (
Zea mays Maize ( ; ''Zea mays'' subsp. ''mays'', from es, maíz after tnq, mahiz), also known as corn (North American and Australian English), is a cereal grain first domesticated by indigenous peoples in southern Mexico about 10,000 years ago. Th ...
)'' * Poplar (''
Populus trichocarpa ''Populus trichocarpa'', the black cottonwood, western balsam-poplar or California poplar, is a deciduous broadleaf tree species native to western North America. It is used for timber, and is notable as a model organism in plant biology. Desc ...
'') * ''
SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
''


Network properties

Protein interaction networks can be analyzed with the same tool as other networks. In fact, they share many properties with biological or
social networks A social network is a social structure made up of a set of social actors (such as individuals or organizations), sets of dyadic ties, and other social interactions between actors. The social network perspective provides a set of methods for an ...
. Some of the main characteristics are as follows.


Degree distribution

The degree distribution describes the number of proteins that have a certain number of connections. Most protein interaction networks show a scale-free (
power law In statistics, a power law is a Function (mathematics), functional relationship between two quantities, where a Relative change and difference, relative change in one quantity results in a proportional relative change in the other quantity, inde ...
) degree distribution where the connectivity distribution P(k) ~ k−γ with k being the degree. This relationship can also be seen as a straight line on a log-log plot since, the above equation is equal to log(P(k)) ~ —y•log(k). One characteristic of such distributions is that there are many proteins with few interactions and few proteins that have many interactions, the latter being called "hubs".


Hubs

Highly connected nodes (proteins) are called hubs. Han et al. have coined the term "party hub" for hubs whose expression is correlated with its interaction partners. Party hubs also connect proteins within functional modules such as protein complexes. In contrast, "date hubs" do not exhibit such a correlation and appear to connect different functional modules. Party hubs are found predominantly in AP/MS data sets, whereas date hubs are found predominantly in binary interactome network maps. Note that the validity of the date hub/party hub distinction was disputed. Party hubs generally consist of multi-interface proteins whereas date hubs are more frequently single-interaction interface proteins. Consistent with a role for date-hubs in connecting different processes, in yeast the number of binary interactions of a given protein is correlated to the number of phenotypes observed for the corresponding mutant gene in different physiological conditions.


Modules

Nodes involved in the same biochemical process are highly interconnected.


Evolution

The evolution of interactome complexity is delineated in a study published in ''Nature''. In this study it is first noted that the boundaries between
prokaryotes A prokaryote () is a single-celled organism that lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek πρό (, 'before') and κάρυον (, 'nut' or 'kernel').Campbell, N. "Biology:Concepts & Connec ...
, unicellular
eukaryotes Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
and multicellular eukaryotes are accompanied by orders-of-magnitude reductions in effective population size, with concurrent amplifications of the effects of
random genetic drift Genetic drift, also known as allelic drift or the Wright effect, is the change in the frequency of an existing gene variant (allele) in a population due to random chance. Genetic drift may cause gene variants to disappear completely and there ...
. The resultant decline in the efficiency of selection seems to be sufficient to influence a wide range of attributes at the genomic level in a nonadaptive manner. The Nature study shows that the variation in the power of random genetic drift is also capable of influencing phylogenetic diversity at the subcellular and cellular levels. Thus, population size would have to be considered as a potential determinant of the mechanistic pathways underlying long-term phenotypic evolution. In the study it is further shown that a phylogenetically broad inverse relation exists between the power of drift and the structural integrity of protein subunits. Thus, the accumulation of mildly deleterious mutations in populations of small size induces secondary selection for protein–protein interactions that stabilize key gene functions, mitigating the structural degradation promoted by inefficient selection. By this means, the complex protein architectures and interactions essential to the genesis of phenotypic diversity may initially emerge by non-adaptive mechanisms.


Criticisms, challenges, and responses

Kiemer and Cesareni raise the following concerns with the state (circa 2007) of the field especially with the comparative interactomic: The experimental procedures associated with the field are error prone leading to "noisy results". This leads to 30% of all reported interactions being artifacts. In fact, two groups using the same techniques on the same organism found less than 30% interactions in common. However, some authors have argued that such non-reproducibility results from the extraordinary sensitivity of various methods to small experimental variation. For instance, identical conditions in Y2H assays result in very different interactions when different Y2H vectors are used. Techniques may be biased, i.e. the technique determines which interactions are found. In fact, any method has built in biases, especially protein methods. Because every protein is different no method can capture the properties of each protein. For instance, most analytical methods that work fine with soluble proteins deal poorly with membrane proteins. This is also true for Y2H and AP/MS technologies. Interactomes are not nearly complete with perhaps the exception of ''S. cerevisiae.'' This is not really a criticism as any scientific area is "incomplete" initially until the methodologies have been improved. Interactomics in 2015 is where genome sequencing was in the late 1990s, given that only a few interactome datasets are available (see table above). While genomes are stable, interactomes may vary between tissues, cell types, and developmental stages. Again, this is not a criticism, but rather a description of the challenges in the field. It is difficult to match evolutionarily related proteins in distantly related species. While homologous DNA sequences can be found relatively easily, it is much more difficult to predict homologous interactions ("interologs") because the homologs of two interacting proteins do not need to interact. For instance, even within a proteome two proteins may interact but their paralogs may not. Each protein–protein interactome may represent only a partial sample of potential interactions, even when a supposedly definitive version is published in a scientific journal. Additional factors may have roles in protein interactions that have yet to be incorporated in interactomes. The binding strength of the various protein interactors, microenvironmental factors, sensitivity to various procedures, and the physiological state of the cell all impact protein–protein interactions, yet are usually not accounted for in interactome studies.


See also

*
Bioinformatics Bioinformatics () is an interdisciplinary field that develops methods and software tools for understanding biological data, in particular when the data sets are large and complex. As an interdisciplinary field of science, bioinformatics combi ...
,
Omics The branches of science known informally as omics are various disciplines in biology whose names end in the suffix '' -omics'', such as genomics, proteomics, metabolomics, metagenomics, phenomics and transcriptomics. Omics aims at the collect ...
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Proteomics Proteomics is the large-scale study of proteins. Proteins are vital parts of living organisms, with many functions such as the formation of structural fibers of muscle tissue, enzymatic digestion of food, or synthesis and replication of DNA. In ...
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Genomics Genomics is an interdisciplinary field of biology focusing on the structure, function, evolution, mapping, and editing of genomes. A genome is an organism's complete set of DNA, including all of its genes as well as its hierarchical, three-dim ...
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Biological network A biological network is a method of representing systems as complex sets of binary interactions or relations between various biological entities. In general, networks or graphs are used to capture relationships between entities or objects. A typi ...
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BioPlex BioPlex (biophysical interactions of ORFeome-based complexes) is an open access resource for studying protein-protein interactions. It is the result of collaborations between Harvard Medical School and Biogen. BioPlex 1.0 reported 23,744 interact ...
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Connectome A connectome () is a comprehensive map of neural connections in the brain, and may be thought of as its "wiring diagram". An organism's nervous system is made up of neurons which communicate through synapses. A connectome is constructed by tr ...
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Glossary of graph theory This is a glossary of graph theory. Graph theory is the study of graphs, systems of nodes or vertices connected in pairs by lines or edges. Symbols A B ...
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Human interactome The human interactome is the set of protein–protein interactions (the interactome) that occur in human cells. The sequencing of reference genomes, in particular the Human Genome Project, has revolutionized human genetics, molecular biology, and ...
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Interaction network In molecular biology, an interactome is the whole set of molecular interactions in a particular cell. The term specifically refers to physical interactions among molecules (such as those among proteins, also known as protein–protein interactions, ...
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List of omics topics in biology Inspired by the terms genome and genomics, other words to describe complete biological datasets, mostly sets of biomolecules originating from one organism, have been coined with the suffix '' -ome'' and ''-omics''. Some of these terms are related ...
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Mathematical biology Mathematical and theoretical biology, or biomathematics, is a branch of biology which employs theoretical analysis, mathematical models and abstractions of the living organisms to investigate the principles that govern the structure, development a ...
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Metabolic network A metabolic network is the complete set of metabolic and physical processes that determine the physiological and biochemical properties of a cell. As such, these networks comprise the chemical reactions of metabolism, the metabolic pathways, as w ...
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Metabolic network modelling Metabolic network modelling, also known as metabolic network reconstruction or metabolic pathway analysis, allows for an in-depth insight into the molecular mechanisms of a particular organism. In particular, these models correlate the genome wi ...
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Metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reac ...
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Network medicine Network medicine is the application of network science towards identifying, preventing, and treating diseases. This field focuses on using network topology and network dynamics towards identifying diseases and developing medical drugs. Biologica ...
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Protein–protein interaction Protein–protein interactions (PPIs) are physical contacts of high specificity established between two or more protein molecules as a result of biochemical events steered by interactions that include electrostatic forces, hydrogen bonding and th ...
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Systems biology Systems biology is the computational modeling, computational and mathematical analysis and modeling of complex biological systems. It is a biology-based interdisciplinary field of study that focuses on complex interactions within biological syst ...
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Chemoproteomics Chemoproteomics entails a broad array of techniques used to identify and interrogate protein- small molecule interactions. Chemoproteomics complements phenotypic drug discovery, a paradigm that aims to discover lead compounds on the basis of allev ...


References


Further reading

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External links


Interactome web servers


Protinfo PPC
predicts the atomic 3D structure of protein protein complexes. * IBIS (server) reports, predicts and integrates multiple types of conserved interactions for proteins.


Interactome visualization tools


GPS-Prot
Web-based data visualization for protein interactions * PINV


Interactome databases


BioGRID
database
mentha
the interactome browser {{cite journal , last1 = Calderone , display-authors=etal , year = 2013 , title = mentha: a resource for browsing integrated protein-interaction networks , journal = Nature Methods , volume = 10 , issue = 8, pages = 690–691 , doi = 10.1038/nmeth.2561 , pmid = 23900247, s2cid=9733108 , url=https://zenodo.org/record/924817
IntAct: The Molecular Interaction Database

Interactome.org
— a dedicated interactome web site. Bioinformatics Molecular biology Systems biology Protein complexes