
Protein–protein interactions (PPIs) are physical contacts of high specificity established between two or more
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
molecules as a result of biochemical events steered by interactions that include
electrostatic forces,
hydrogen bond
In chemistry, a hydrogen bond (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, Covalent bond, covalently b ...
ing and the
hydrophobic effect
The hydrophobic effect is the observed tendency of nonpolar substances to aggregate in an aqueous solution and to be excluded by water. The word hydrophobic literally means "water-fearing", and it describes the segregation of water and nonpola ...
. Many are physical contacts with molecular associations between chains that occur in a cell or in a living organism in a specific biomolecular context.
Proteins rarely act alone as their functions tend to be regulated. Many molecular processes within a cell are carried out by
molecular machine
Molecular machines are a class of molecules typically described as an assembly of a discrete number of molecular components intended to produce mechanical movements in response to specific stimuli, mimicking macromolecular devices such as switch ...
s that are built from numerous protein components organized by their PPIs. These physiological interactions make up the so-called
interactomics of the organism, while aberrant PPIs are the basis of multiple aggregation-related diseases, such as
Creutzfeldt–Jakob and
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
s.
PPIs have been studied with
many methods and from different perspectives:
biochemistry
Biochemistry, or biological chemistry, is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology, a ...
,
quantum chemistry
Quantum chemistry, also called molecular quantum mechanics, is a branch of physical chemistry focused on the application of quantum mechanics to chemical systems, particularly towards the quantum-mechanical calculation of electronic contributions ...
,
molecular dynamics
Molecular dynamics (MD) is a computer simulation method for analyzing the Motion (physics), physical movements of atoms and molecules. The atoms and molecules are allowed to interact for a fixed period of time, giving a view of the dynamics ( ...
,
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...
, among others.
All this information enables the creation of large protein interaction networks
– similar to
metabolic
Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the ...
or
genetic/epigenetic networks – that empower the current knowledge on
biochemical cascade
A biochemical cascade, also known as a signaling cascade or signaling pathway, is a series of chemical reactions that occur within a biological cell when initiated by a stimulus. This stimulus, known as a first messenger, acts on a receptor that ...
s and molecular etiology of disease, as well as the discovery of putative protein targets of therapeutic interest.
Examples
Electron transfer proteins
In many metabolic reactions, a protein that acts as an electron carrier binds to an enzyme that acts as its
reductase
In biochemistry, an oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule, the reductant, also called the electron donor, to another, the oxidant, also called the electron acceptor. This group of enzymes usually uti ...
. After it receives an electron, it dissociates and then binds to the next enzyme that acts as its
oxidase
In biochemistry, an oxidase is an oxidoreductase (any enzyme that catalyzes a redox reaction) that uses dioxygen (O2) as the electron acceptor. In reactions involving donation of a hydrogen atom, oxygen is reduced to water (H2O) or hydrogen peroxid ...
(i.e. an acceptor of the electron). These interactions between proteins are dependent on highly specific binding between proteins to ensure efficient electron transfer. Examples: mitochondrial oxidative phosphorylation chain system components cytochrome c-reductase /
cytochrome c / cytochrome c oxidase; microsomal and mitochondrial P450 systems.
In the case of the mitochondrial P450 systems, the specific residues involved in the binding of the electron transfer protein
adrenodoxin
Adrenal ferredoxin (also adrenodoxin (ADX), adrenodoxin, mitochondrial, hepatoredoxin, ferredoxin-1 (FDX1)) is a protein that in humans is encoded by the ''FDX1'' gene. In addition to the expressed gene at this chromosomal locus (11q22), there ...
to its reductase were identified as two basic Arg residues on the surface of the reductase and two acidic Asp residues on the adrenodoxin.
More recent work on the phylogeny of the reductase has shown that these residues involved in protein–protein interactions have been conserved throughout the evolution of this enzyme.
Signal transduction
The activity of the cell is regulated by extracellular signals. Signal propagation inside and/or along the interior of cells depends on PPIs between the various signaling molecules. The recruitment of signaling pathways through PPIs is called
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...
and plays a fundamental role in many biological processes and in many diseases including
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
and cancer.
Membrane transport
A protein may be carrying another protein (for example, from
cytoplasm
The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...
to
nucleus
Nucleus (: nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
*Atomic nucleus, the very dense central region of an atom
*Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucleu ...
or vice versa in the case of the
nuclear pore
The nuclear pore complex (NPC), is a large protein complex giving rise to the nuclear pore. A great number of nuclear pores are studded throughout the nuclear envelope that surrounds the eukaryote cell nucleus. The pores enable the nuclear tran ...
importins).
Cell metabolism
In many biosynthetic processes
enzymes
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as pro ...
interact with each other to produce small compounds or other macromolecules.
Muscle contraction
Physiology of
muscle contraction
Muscle contraction is the activation of Tension (physics), tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in musc ...
involves several interactions.
Myosin
Myosins () are a Protein family, family of motor proteins (though most often protein complexes) best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are adenosine triphosphate, ATP- ...
filaments act as
molecular motor
Molecular motors are natural (biological) or artificial molecular machines that are the essential agents of movement in living organisms. In general terms, a motor is a device that consumes energy in one form and converts it into motion or mech ...
s and by binding to
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...
enables filament sliding. Furthermore, members of the
skeletal muscle
Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...
lipid droplet-associated proteins family associate with other proteins, as activator of
adipose triglyceride lipase
Adipose triglyceride lipase, also known as patatin-like phospholipase domain-containing protein 2 and ATGL, is an enzyme that in humans is encoded by the ''PNPLA2'' gene. ATGL catalyses the first reaction of lipolysis, where triacylglycerols are ...
and its
coactivator
A coactivator is a type of transcriptional coregulator that binds to an activator (a transcription factor) to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA ...
comparative gene identification-58, to regulate
lipolysis
Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolysis, hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in Adipose tissue, fat adip ...
in skeletal muscle
Types
To describe the types of protein–protein interactions (PPIs) it is important to consider that proteins can interact in a "transient" way (to produce some specific effect in a short time, like signal transduction) or to interact with other proteins in a "stable" way to form complexes that become molecular machines within the living systems. A protein complex assembly can result in the formation of
homo-oligomeric or hetero-oligomeric complexes. In addition to the conventional complexes, as enzyme-inhibitor and antibody-antigen, interactions can also be established between domain-domain and domain-peptide. Another important distinction to identify protein–protein interactions is the way they have been determined, since there are techniques that measure direct physical interactions between protein pairs, named “binary” methods, while there are other techniques that measure physical interactions among groups of proteins, without pairwise determination of protein partners, named “co-complex” methods.
Homo-oligomers vs. hetero-oligomers
Homo-oligomers are macromolecular complexes constituted by only one type of
protein subunit
In structural biology, a protein subunit is a polypeptide chain or single protein molecule that assembles (or "''coassembles''") with others to form a protein complex.
Large assemblies of proteins such as viruses often use a small number of t ...
. Protein subunits assembly is guided by the establishment of
non-covalent interactions
In chemistry, a non-covalent interaction differs from a covalent bond in that it does not involve the sharing of electrons, but rather involves more dispersed variations of electromagnetic interactions between molecules or within a molecule. The ...
in the
quaternary structure of the protein. Disruption of homo-oligomers in order to return to the initial individual
monomers
A monomer ( ; ''wikt:mono-, mono-'', "one" + ''wikt:-mer, -mer'', "part") is a molecule that can chemical reaction, react together with other monomer molecules to form a larger polymer chain or two- or three-dimensional network in a process called ...
often requires denaturation of the complex.
Several
enzymes
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as pro ...
,
carrier proteins, scaffolding proteins, and transcriptional regulatory factors carry out their functions as homo-oligomers.
Distinct protein subunits interact in hetero-oligomers, which are essential to control several cellular functions. The importance of the communication between heterologous proteins is even more evident during cell signaling events and such interactions are only possible due to structural domains within the proteins (as described below).
Stable interactions vs. transient interactions
Stable interactions involve proteins that interact for a long time, taking part of permanent complexes as subunits, in order to carry out functional roles. These are usually the case of homo-oligomers (e.g.
cytochrome c), and some hetero-oligomeric proteins, as the subunits of
ATPase
ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, ATP hydrolase, adenosine triphosphatase) are a class of enzymes that catalyze the decomposition of ATP into ADP and a free phosphate ion or ...
. On the other hand, a protein may interact briefly and in a
reversible manner with other proteins in only certain cellular contexts –
cell type
A cell type is a classification used to identify cells that share morphological or phenotypical features. A multicellular organism may contain cells of a number of widely differing and specialized cell types, such as muscle cells and skin cell ...
,
cell cycle stage, external factors, presence of other binding proteins, etc. – as it happens with most of the proteins involved in
biochemical cascade
A biochemical cascade, also known as a signaling cascade or signaling pathway, is a series of chemical reactions that occur within a biological cell when initiated by a stimulus. This stimulus, known as a first messenger, acts on a receptor that ...
s. These are called transient interactions. For example, some G protein–coupled receptors only transiently bind to G
i/o proteins when they are activated by extracellular ligands,
while some G
q-coupled receptors, such as muscarinic receptor M3, pre-couple with G
q proteins prior to the receptor-ligand binding.
Interactions between intrinsically disordered protein regions to globular protein domains (i.e.
MoRFs) are transient interactions.
Covalent vs. non-covalent
Covalent interactions are those with the strongest association and are formed by
disulphide bonds or
electron sharing. While rare, these interactions are determinant in some
posttranslational modifications
In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translate mRNA in ...
, as
ubiquitination
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...
and
SUMOylation
In molecular biology, SUMO (Small Ubiquitin-like Modifier) proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. This process is called SUMOylation (pronounced ...
. Non-covalent bonds are usually established during transient interactions by the combination of weaker bonds, such as
hydrogen bonds
In chemistry, a hydrogen bond (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, covalently bonded to a mo ...
, ionic interactions,
Van der Waals force
In molecular physics and chemistry, the van der Waals force (sometimes van der Waals' force) is a distance-dependent interaction between atoms or molecules. Unlike ionic or covalent bonds, these attractions do not result from a chemical elec ...
s, or hydrophobic bonds.
Role of water
Water molecules play a significant role in the interactions between proteins. The crystal structures of complexes, obtained at high resolution from different but homologous proteins, have shown that some interface water molecules are conserved between homologous complexes. The majority of the interface water molecules make hydrogen bonds with both partners of each complex. Some interface amino acid residues or atomic groups of one protein partner engage in both direct and water mediated interactions with the other protein partner. Doubly indirect interactions, mediated by two water molecules, are more numerous in the homologous complexes of low affinity. Carefully conducted mutagenesis experiments, e.g. changing a tyrosine residue into a phenylalanine, have shown that water mediated interactions can contribute to the energy of interaction. Thus, water molecules may facilitate the interactions and cross-recognitions between proteins.
Structure
The
molecular structure
Molecular geometry is the three-dimensional arrangement of the atoms that constitute a molecule. It includes the general shape of the molecule as well as bond lengths, bond angles, torsional angles and any other geometrical parameters that det ...
s of many protein complexes have been unlocked by the technique of
X-ray crystallography
X-ray crystallography is the experimental science of determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to Diffraction, diffract in specific directions. By measuring th ...
.
The first structure to be solved by this method was that of
sperm whale
The sperm whale or cachalot (''Physeter macrocephalus'') is the largest of the toothed whales and the largest toothed predator. It is the only living member of the Genus (biology), genus ''Physeter'' and one of three extant species in the s ...
myoglobin
Myoglobin (symbol Mb or MB) is an iron- and oxygen-binding protein found in the cardiac and skeletal muscle, skeletal Muscle, muscle tissue of vertebrates in general and in almost all mammals. Myoglobin is distantly related to hemoglobin. Compar ...
by
Sir John Cowdery Kendrew. In this technique the angles and intensities of a beam of X-rays diffracted by crystalline atoms are detected in a film, thus producing a three-dimensional picture of the density of electrons within the crystal.
Later,
nuclear magnetic resonance
Nuclear magnetic resonance (NMR) is a physical phenomenon in which nuclei in a strong constant magnetic field are disturbed by a weak oscillating magnetic field (in the near field) and respond by producing an electromagnetic signal with a ...
also started to be applied with the aim of unravelling the molecular structure of protein complexes. One of the first examples was the structure of calmodulin-binding domains bound to
calmodulin
Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all Eukaryote, eukaryotic cells. It is an intracellular target of the Second messenger system, sec ...
.
This technique is based on the study of magnetic properties of atomic nuclei, thus determining physical and chemical properties of the correspondent atoms or the molecules. Nuclear magnetic resonance is advantageous for characterizing weak PPIs.
Protein-protein interaction domains
Some proteins have specific
structural domains or
sequence motifs that provide binding to other proteins. Here are some examples of such domains:
* ''Src homology 2 (SH2) domain ''
:SH2 domains are structurally composed by three-stranded twisted beta sheet sandwiched flanked by two alpha-helices. The existence of a deep binding pocket with high affinity for
phosphotyrosine, but not for
phosphoserine or
phosphothreonine, is essential for the recognition of tyrosine phosphorylated proteins, mainly autophosphorylated
growth factor
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for ...
receptors. Growth factor receptor binding proteins and
phospholipase C
Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role i ...
γ are examples of proteins that have SH2 domains.
* ''Src homology 3 (SH3) domain ''
:Structurally, SH3 domains are constituted by a beta barrel formed by two orthogonal beta sheets and three anti-parallel beta strands. These domains recognize
proline
Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...
enriched sequences, as polyproline type II helical structure (PXXP motifs) in cell signaling proteins like protein
tyrosine kinases
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...
and the growth factor receptor bound protein 2 (
Grb2
Growth factor receptor-bound protein 2, also known as Grb2, is an adaptor protein involved in signal transduction/ cell communication. In humans, the GRB2 protein is encoded by the ''GRB2'' gene.
The protein encoded by this gene binds recepto ...
).
* ''Phosphotyrosine-binding (PTB) domain ''
:PTB domains interact with sequences that contain a phosphotyrosine group. These domains can be found in the
insulin receptor substrate.
* ''LIM domain ''
:LIM domains were initially identified in three
homeodomain transcription factors (lin11, is11, and mec3). In addition to this
homeodomain proteins and other proteins involved in development, LIM domains have also been identified in non-homeodomain proteins with relevant roles in
cellular differentiation
Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellula ...
, association with
cytoskeleton
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
and
senescence
Senescence () or biological aging is the gradual deterioration of Function (biology), functional characteristics in living organisms. Whole organism senescence involves an increase in mortality rate, death rates or a decrease in fecundity with ...
. These domains contain a tandem cysteine-rich
Zn2+-finger motif and embrace the
consensus sequence
In molecular biology and bioinformatics, the consensus sequence (or canonical sequence) is the calculated sequence of most frequent residues, either nucleotide or amino acid, found at each position in a sequence alignment. It represents the result ...
CX2CX16-23HX2CX2CX2CX16-21CX2C/H/D. LIM domains bind to PDZ domains, bHLH transcription factors, and other LIM domains.
* ''Sterile alpha motif (SAM) domain ''
:SAM domains are composed by five helices forming a compact package with a conserved
hydrophobic core
The hydrophobic effect is the observed tendency of nonpolar substances to aggregate in an aqueous solution and to be excluded by water#Properties, water. The word hydrophobic literally means "water-fearing", and it describes the Segregation in m ...
. These domains, which can be found in the
Eph receptor
Eph receptors (Ephs, after erythropoietin-producing human hepatocellular receptors) are a group of receptors that are activated in response to binding with Eph receptor-interacting proteins (Ephrins). Ephs form the largest known subfamily of rec ...
and the stromal interaction molecule (
STIM) for example, bind to non-SAM domain-containing proteins and they also appear to have the ability to bind
RNA
Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...
.
* ''PDZ domain ''
:PDZ domains were first identified in three guanylate kinases: PSD-95, DlgA and ZO-1. These domains recognize carboxy-terminal tri-peptide motifs (S/TXV), other
PDZ domain
The PDZ domain is a common structural domain of 80-90 Amino acid, amino-acids found in the Signal transduction, signaling proteins of bacteria, yeast, plants, viruses and animals. Proteins containing PDZ domains play a key role in anchoring recept ...
s or
LIM domain
LIM domains are protein structural domains, composed of two contiguous zinc fingers, separated by a two-amino acid residue hydrophobic linker. The domain name is an acronym of the three genes in which it was first identified (LIN-11, Isl-1 and M ...
s and bind them through a short peptide sequence that has a
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...
hydrophobic residue. Some of the proteins identified as having PDZ domains are scaffolding proteins or seem to be involved in ion receptor assembling and receptor-enzyme complexes formation.
* ''FERM domain ''
:FERM domains contain basic residues capable of binding
PtdIns(4,5)P2.
Talin and
focal adhesion kinase (FAK) are two of the proteins that present FERM domains.
* ''Calponin homology (CH) domain ''
:CH domains are mainly present in cytoskeletal proteins as
parvin.
* ''Pleckstrin homology domain ''
:Pleckstrin homology domains bind to phosphoinositides and acid domains in signaling proteins.
* ''WW domain ''
:WW domains bind to proline enriched sequences.
* ''WSxWS motif ''
:Found in cytokine receptors
Properties of the interface
The study of the molecular structure can give fine details about the interface that enables the interaction between proteins. When characterizing PPI interfaces it is important to take into account the type of complex.
Parameters evaluated include size (measured in absolute dimensions
Å2 or in
solvent-accessible surface area (SASA)), shape, complementarity between surfaces, residue interface propensities, hydrophobicity, segmentation and secondary structure, and conformational changes on complex formation.
The great majority of PPI interfaces reflects the composition of protein surfaces, rather than the protein cores, in spite of being frequently enriched in hydrophobic residues, particularly in aromatic residues.
PPI interfaces are dynamic and frequently planar, although they can be globular and protruding as well.
Based on three structures –
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
dimer,
trypsin
Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the dig ...
-pancreatic trypsin inhibitor complex, and
oxyhaemoglobin –
Cyrus Chothia and Joel Janin found that between 1,130 and 1,720 Å
2 of surface area was removed from contact with water indicating that hydrophobicity is a major factor of stabilization of PPIs.
Later studies refined the buried surface area of the majority of interactions to 1,600±350 Å
2. However, much larger interaction interfaces were also observed and were associated with
significant changes in conformation of one of the interaction partners.
PPIs interfaces exhibit both shape and electrostatic complementarity.
Regulation
* Protein concentration, which in turn are affected by expression levels and degradation rates;
* Protein affinity for proteins or other binding ligands;
* Ligands concentrations (
substrates,
ions
An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
, etc.);
* Presence of other
proteins
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, re ...
,
nucleic acids
Nucleic acids are large biomolecules that are crucial in all cells and viruses. They are composed of nucleotides, which are the monomer components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main classes of nucleic a ...
, and
ions
An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
;
*
Electric field
An electric field (sometimes called E-field) is a field (physics), physical field that surrounds electrically charged particles such as electrons. In classical electromagnetism, the electric field of a single charge (or group of charges) descri ...
s around proteins.
* Occurrence of covalent modifications;
Experimental methods
There are a multitude of methods to detect them.
Each of the approaches has its own strengths and weaknesses, especially with regard to the
sensitivity and specificity
In medicine and statistics, sensitivity and specificity mathematically describe the accuracy of a test that reports the presence or absence of a medical condition. If individuals who have the condition are considered "positive" and those who do ...
of the method. The most conventional and widely used high-throughput methods are
yeast two-hybrid screening and
affinity purification coupled to
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 used ...
.
Yeast two-hybrid screening
This system was firstly described in 1989 by Fields and Song using ''Saccharomyces cerevisiae'' as biological model. Yeast two hybrid allows the identification of pairwise PPIs (binary method) ''in vivo'', in which the two proteins are tested for biophysically direct interaction. The Y2H is based on the functional reconstitution of the yeast transcription factor Gal4 and subsequent activation of a selective reporter such as His3. To test two proteins for interaction, two protein expression constructs are made: one protein (X) is fused to the Gal4 DNA-binding domain (DB) and a second protein (Y) is fused to the Gal4 activation domain (AD). In the assay, yeast cells are transformed with these constructs. Transcription of reporter genes does not occur unless bait (DB-X) and prey (AD-Y) interact with each other and form a functional Gal4 transcription factor. Thus, the interaction between proteins can be inferred by the presence of the products resultant of the reporter gene expression.
In cases in which the reporter gene expresses enzymes that allow the yeast to synthesize essential amino acids or nucleotides, yeast growth under selective media conditions indicates that the two proteins tested are interacting. Recently, software to detect and prioritize protein interactions was published.
Despite its usefulness, the yeast two-hybrid system has limitations. It uses yeast as main host system, which can be a problem when studying proteins that contain mammalian-specific post-translational modifications. The number of PPIs identified is usually low because of a high false negative rate; and, understates
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 ...
, for example.
In initial studies that utilized Y2H, proper controls for false positives (e.g. when DB-X activates the reporter gene without the presence of AD-Y) were frequently not done, leading to a higher than normal false positive rate. An empirical framework must be implemented to control for these false positives. Limitations in lower coverage of membrane proteins have been overcoming by the emergence of yeast two-hybrid variants, such as the membrane yeast two-hybrid (MYTH)
and the split-ubiquitin system,
which are not limited to interactions that occur in the nucleus; and, the bacterial two-hybrid system, performed in bacteria;
Affinity purification coupled to mass spectrometry
Affinity purification coupled to mass spectrometry mostly detects stable interactions and thus better indicates functional in vivo PPIs.
This method starts by purification of the tagged protein, which is expressed in the cell usually at ''in vivo'' concentrations, and its interacting proteins (affinity purification). One of the most advantageous and widely used methods to purify proteins with very low contaminating background is the
tandem affinity purification, developed by Bertrand Seraphin and Matthias Mann and respective colleagues. PPIs can then be analysed by mass spectrometry using different methods: chemical incorporation, biological or metabolic incorporation (SILAC), and label-free methods.
Furthermore,
network theory
In mathematics, computer science, and network science, network theory is a part of graph theory. It defines networks as Graph (discrete mathematics), graphs where the vertices or edges possess attributes. Network theory analyses these networks ...
has been used to study the whole set of identified protein–protein interactions in cells.
Nucleic acid programmable protein array (NAPPA)
This system was first developed by LaBaer and colleagues in 2004 by using in vitro transcription and translation system. They use DNA template encoding the gene of interest fused with GST protein, and it was immobilized in the solid surface. Anti-GST antibody and biotinylated plasmid DNA were bounded in aminopropyltriethoxysilane (APTES)-coated slide. BSA can improve the binding efficiency of DNA. Biotinylated plasmid DNA was bound by avidin. New protein was synthesized by using cell-free expression system i.e. rabbit reticulocyte lysate (RRL), and then the new protein was captured through anti-GST antibody bounded on the slide. To test protein–protein interaction, the targeted protein cDNA and query protein cDNA were immobilized in a same coated slide. By using in vitro transcription and translation system, targeted and query protein was synthesized by the same extract. The targeted protein was bound to array by antibody coated in the slide and query protein was used to probe the array. The query protein was tagged with hemagglutinin (HA) epitope. Thus, the interaction between the two proteins was visualized with the antibody against HA.
Intragenic complementation
When multiple copies of a polypeptide encoded by a
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
form a complex, this protein structure is referred to as a multimer. When a multimer is formed from polypeptides produced by two different
mutant
In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It i ...
allele
An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule.
Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...
s of a particular gene, the mixed multimer may exhibit greater functional activity than the unmixed multimers formed by each of the mutants alone. In such a case, the phenomenon is referred to as
intragenic complementation (also called inter-allelic complementation). Intragenic complementation has been demonstrated in many different genes in a variety of organisms including the fungi ''
Neurospora crassa
''Neurospora crassa'' is a type of red bread mold of the phylum Ascomycota. The genus name, meaning 'nerve spore' in Greek, refers to the characteristic striations on the spores. The first published account of this fungus was from an infestatio ...
'', ''
Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungal microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have be ...
'' and ''
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 ...
''; the bacterium ''
Salmonella
''Salmonella'' is a genus of bacillus (shape), rod-shaped, (bacillus) Gram-negative bacteria of the family Enterobacteriaceae. The two known species of ''Salmonella'' are ''Salmonella enterica'' and ''Salmonella bongori''. ''S. enterica'' ...
typhimurium''; the virus
bacteriophage T4
Escherichia virus T4 is a species of bacteriophages that infect ''Escherichia coli'' bacteria. It is a double-stranded DNA virus in the subfamily '' Tevenvirinae'' of the family '' Straboviridae''. T4 is capable of undergoing only a lytic li ...
, an RNA virus
and humans.
In such studies, numerous
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, ...
s defective in the same gene were often isolated and mapped in a linear order on the basis of
recombination frequencies to form a
genetic map
Genetic linkage is the tendency of DNA sequences that are close together on a chromosome to be inherited together during the meiosis phase of sexual reproduction. Two genetic markers that are physically near to each other are unlikely to be separ ...
of the gene. Separately, the mutants were tested in pairwise combinations to measure complementation. An analysis of the results from such studies led to the conclusion that intragenic complementation, in general, arises from the interaction of differently defective polypeptide monomers to form a multimer.
Genes that encode multimer-forming polypeptides appear to be common. One interpretation of the data is that polypeptide monomers are often aligned in the multimer in such a way that mutant polypeptides defective at nearby sites in the genetic map tend to form a mixed multimer that functions poorly, whereas mutant polypeptides defective at distant sites tend to form a mixed multimer that functions more effectively. Direct interaction of two nascent proteins emerging from nearby
ribosome
Ribosomes () are molecular machine, macromolecular machines, found within all cell (biology), cells, that perform Translation (biology), biological protein synthesis (messenger RNA translation). Ribosomes link amino acids together in the order s ...
s appears to be a general mechanism for homo-oligomer (multimer) formation.
Hundreds of protein oligomers were identified that assemble in human cells by such an interaction.
[ The most prevalent form of interaction is between the N-terminal regions of the interacting proteins. Dimer formation appears to be able to occur independently of dedicated assembly machines. The intermolecular forces likely responsible for self-recognition and multimer formation were discussed by Jehle.]
Other potential methods
Diverse techniques to identify PPIs have been emerging along with technology progression. These include co-immunoprecipitation, protein microarrays, analytical ultracentrifugation Analytical ultracentrifugation is an analytical technique which combines an ultracentrifuge with optical monitoring systems.
In an analytical ultracentrifuge (commonly abbreviated as AUC), a sample’s sedimentation profile is monitored in real tim ...
, light scattering
In physics, scattering is a wide range of physical processes where moving particles or radiation of some form, such as light or sound, are forced to deviate from a straight trajectory by localized non-uniformities (including particles and radia ...
, fluorescence spectroscopy
Fluorescence spectroscopy (also known as fluorimetry or spectrofluorometry) is a type of electromagnetic spectroscopy that analyzes fluorescence from a sample. It involves using a beam of light, usually ultraviolet light, that excites the electro ...
, luminescence-based mammalian interactome mapping (LUMIER), resonance-energy transfer systems, mammalian protein–protein interaction trap, electro-switchable biosurfaces, protein–fragment complementation assay, as well as real-time label-free measurements by surface plasmon resonance
Surface plasmon resonance (SPR) is a phenomenon that occurs where electrons in a thin metal sheet become excited by light that is directed to the sheet with a particular angle of incidence (optics), angle of incidence, and then travel parallel to ...
, and calorimetry
In chemistry and thermodynamics, calorimetry () is the science or act of measuring changes in '' state variables'' of a body for the purpose of deriving the heat transfer associated with changes of its state due, for example, to chemical reac ...
.
Computational methods
Computational prediction of protein–protein interactions
The experimental detection and characterization of PPIs is labor-intensive and time-consuming. However, many PPIs can be also predicted computationally, usually using experimental data as a starting point. However, methods have also been developed that allow the prediction of PPI de novo, that is without prior evidence for these interactions.
Genomic context methods
'' The Rosetta Stone or Domain Fusion method'' is based on the hypothesis that interacting proteins are sometimes fused into a single protein in another genome. Therefore, we can predict if two proteins may be interacting by determining if they each have non-overlapping sequence similarity to a region of a single protein sequence in another genome.
'' The Conserved Neighborhood method'' is based on the hypothesis that if genes encoding two proteins are neighbors on a chromosome in many genomes, then they are likely functionally related (and possibly physically interacting).
'' The Phylogenetic Profile method'' is based on the hypothesis that if two or more proteins are concurrently present or absent across several genomes, then they are likely functionally related. Therefore, potentially interacting proteins can be identified by determining the presence or absence of genes across many genomes and selecting those genes which are always present or absent together.
Text mining methods
Publicly available information from biomedical documents is readily accessible through the internet and is becoming a powerful resource for collecting known protein–protein interactions (PPIs), PPI prediction and protein docking. Text mining is much less costly and time-consuming compared to other high-throughput techniques. Currently, text mining methods generally detect binary relation
In mathematics, a binary relation associates some elements of one Set (mathematics), set called the ''domain'' with some elements of another set called the ''codomain''. Precisely, a binary relation over sets X and Y is a set of ordered pairs ...
s between interacting proteins from individual sentences using rule/pattern-based information extraction and machine learning
Machine learning (ML) is a field of study in artificial intelligence concerned with the development and study of Computational statistics, statistical algorithms that can learn from data and generalise to unseen data, and thus perform Task ( ...
approaches. A wide variety of text mining applications for PPI extraction and/or prediction are available for public use, as well as repositories which often store manually validated and/or computationally predicted PPIs. Text mining can be implemented in two stages: ''information retrieval'', where texts containing names of either or both interacting proteins are retrieved and ''information extraction,'' where targeted information (interacting proteins, implicated residues, interaction types, etc.) is extracted.
There are also studies using phylogenetic profiling, basing their functionalities on the theory that proteins involved in common pathways co-evolve in a correlated fashion across species. Some more complex text mining methodologies use advanced Natural Language Processing
Natural language processing (NLP) is a subfield of computer science and especially artificial intelligence. It is primarily concerned with providing computers with the ability to process data encoded in natural language and is thus closely related ...
(NLP) techniques and build knowledge networks (for example, considering gene names as nodes and verbs as edges). Other developments involve kernel method
In machine learning, kernel machines are a class of algorithms for pattern analysis, whose best known member is the support-vector machine (SVM). These methods involve using linear classifiers to solve nonlinear problems. The general task of patt ...
s to predict protein interactions.
Machine learning methods
Many computational methods have been suggested and reviewed for predicting protein–protein interactions. Prediction approaches can be grouped into categories based on predictive evidence: protein sequence, comparative genomics
Comparative genomics is a branch of biological research that examines genome sequences across a spectrum of species, spanning from humans and mice to a diverse array of organisms from bacteria to chimpanzees. This large-scale holistic approach c ...
, protein domains, protein tertiary structure, and interaction network topology. The construction of a positive set (known interacting protein pairs) and a negative set (non-interacting protein pairs) is needed for the development of a computational prediction model. Prediction models using machine learning techniques can be broadly classified into two main groups: supervised and unsupervised, based on the labeling of input variables according to the expected outcome.
In 2005, integral membrane proteins of Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungal microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have be ...
were analyzed using the mating-based ubiquitin system (mbSUS). The system detects membrane proteins interactions with extracellular signaling proteins Of the 705 integral membrane proteins 1,985 different interactions were traced that involved 536 proteins. To sort and classify interactions a support vector machine was used to define high medium and low confidence interactions. The split-ubiquitin membrane yeast two-hybrid system uses transcriptional reporters to identify yeast transformants that encode pairs of interacting proteins.
In 2006, random forest
Random forests or random decision forests is an ensemble learning method for statistical classification, classification, regression analysis, regression and other tasks that works by creating a multitude of decision tree learning, decision trees ...
, an example of a supervised technique, was found to be the 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.
As of 2020, a model using residue cluster classes (RCCs), constructed from the 3DID and Negatome databases, resulted in 96-99% correctly classified instances of protein–protein interactions. RCCs are a computational vector space that mimics protein fold space and includes all simultaneously contacted residue sets, which can be used to analyze protein structure-function relation and evolution.
Databases
Large scale identification of PPIs generated hundreds of thousands of interactions, which were collected together in specialized biological databases
Biological databases are libraries of biological sciences, collected from scientific experiments, published literature, high-throughput experiment technology, and computational analysis. They contain information from research areas including geno ...
that are continuously updated in order to provide complete interactomes. The first of these databases was the Database of Interacting Proteins (DIP).
''Primary databases'' collect information about published PPIs proven to exist via small-scale or large-scale experimental methods. Examples: DIP, Biomolecular Interaction Network Database (BIND), Biological General Repository for Interaction Datasets ( BioGRID), Human Protein Reference Database (HPRD), IntAct Molecular Interaction Database, Molecular Interactions Database (MINT), MIPS Protein Interaction Resource on Yeast (MIPS-MPact), and MIPS Mammalian Protein–Protein Interaction Database (MIPS-MPPI).<
''Meta-databases'' normally result from the integration of primary databases information, but can also collect some original data.
''Prediction databases'' include many PPIs that are predicted using several techniques (main article). Examples: Human Protein–Protein Interaction Prediction Database (PIPs), Interlogous Interaction Database (I2D), Known and Predicted Protein–Protein Interactions (STRING-db), and Unified Human Interactive (UniHI).
The aforementioned computational methods all depend on source databases whose data can be extrapolated to predict novel protein–protein interactions''. Coverage'' differs greatly between databases. In general, primary databases have the fewest total protein interactions recorded as they do not integrate data from multiple other databases, while prediction databases have the most because they include other forms of evidence in addition to experimental. For example, the primary database IntAct has 572,063 interactions, the meta-database APID has 678,000 interactions, and the predictive database STRING has 25,914,693 interactions. However, it is important to note that some of the interactions in the STRING database are only predicted by computational methods such as Genomic Context and not experimentally verified.
Interaction networks
Information found in PPIs databases supports the construction of interaction networks. Although the PPI network of a given query protein can be represented in textbooks, diagrams of whole cell PPIs are frankly complex and difficult to generate.
One example of a manually produced molecular interaction map is the Kurt Kohn's 1999 map of cell cycle control. Drawing on Kohn's map, Schwikowski et al. in 2000 published a paper on PPIs in yeast, linking 1,548 interacting proteins determined by two-hybrid screening. They used a layered graph drawing method to find an initial placement of the nodes and then improved the layout using a force-based algorithm.
Bioinformatic tools have been developed to simplify the difficult task of visualizing molecular interaction networks and complement them with other types of data. For instance, Cytoscape
Cytoscape is an Open-source software, open source bioinformatics software platform for Visualization (graphic), visualizing Metabolic network modelling, molecular interaction networks and integrating with gene expression profiles and other state da ...
is an open-source software widely used and many plugins are currently available. Pajek software is advantageous for the visualization and analysis of very large networks.
Identification of functional modules in PPI networks is an important challenge in bioinformatics. Functional modules means a set of proteins that are highly connected
Connected may refer to:
Film and television
* ''Connected'' (2008 film), a Hong Kong remake of the American movie ''Cellular''
* '' Connected: An Autoblogography About Love, Death & Technology'', a 2011 documentary film
* ''Connected'' (2015 TV ...
to each other in PPI network. It is almost similar problem as community detection in social network
A social network is a social structure consisting of a set of social actors (such as individuals or organizations), networks of Dyad (sociology), dyadic ties, and other Social relation, social interactions between actors. The social network per ...
s. There are some methods such as Jactive modules and MoBaS. Jactive modules integrate PPI network and gene expression
Gene expression is the process (including its Regulation of gene expression, regulation) by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, ...
data where as MoBaS integrate PPI network and Genome Wide association Studies.
protein–protein relationships are often the result of multiple types of interactions or are deduced from different approaches, including co-localization, direct interaction, suppressive genetic interaction, additive genetic interaction, physical association, and other associations.
Signed interaction networks
Protein–protein interactions often result in one of the interacting proteins either being 'activated' or 'repressed'. Such effects can be indicated in a PPI network by "signs" (e.g. "activation" or "inhibition"). Although such attributes have been added to networks for a long time, Vinayagam et al. (2014) coined the term ''Signed network'' for them. Signed networks are often expressed by labeling the interaction as either positive or negative. A positive interaction is one where the interaction results in one of the proteins being activated. Conversely, a negative interaction indicates that one of the proteins being inactivated.
Protein–protein interaction networks are often constructed as a result of lab experiments such as yeast two-hybrid screens or 'affinity purification and subsequent mass spectrometry techniques. However these methods do not provide the layer of information needed in order to determine what type of interaction is present in order to be able to attribute signs to the network diagrams.
RNA interference screens
RNA interference
RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known by ...
(RNAi) screens (repression of individual proteins between transcription and translation) are one method that can be utilized in the process of providing signs to the protein–protein interactions. Individual proteins are repressed and the resulting phenotypes are analyzed. A correlating phenotypic relationship (i.e. where the inhibition of either of two proteins results in the same phenotype) indicates a positive, or activating relationship. Phenotypes that do not correlate (i.e. where the inhibition of either of two proteins results in two different phenotypes) indicate a negative or inactivating relationship. If protein A is dependent on protein B for activation then the inhibition of either protein A or B will result in a cell losing the service that is provided by protein A and the phenotypes will be the same for the inhibition of either A or B. If, however, protein A is inactivated by protein B then the phenotypes will differ depending on which protein is inhibited (inhibit protein B and it can no longer inactivate protein A leaving A active however inactivate A and there is nothing for B to activate since A is inactive and the phenotype changes). Multiple RNAi
RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known b ...
screens need to be performed in order to reliably appoint a sign to a given protein–protein interaction. Vinayagam et al. who devised this technique state that a minimum of nine RNAi
RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known b ...
screens are required with confidence increasing as one carries out more screens.
As therapeutic targets
Modulation of PPI is challenging and is receiving increasing attention by the scientific community. Several properties of PPI such as allosteric sites and hotspots, have been incorporated into drug-design strategies. Nevertheless, very few PPIs are directly targeted by FDA
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
-approved small-molecule PPI inhibitors, emphasizing a huge untapped opportunity for drug discovery.
In 2014, Amit Jaiswal and others were able to develop 30 peptides to inhibit recruitment of telomerase towards telomeres by utilizing protein–protein interaction studies. Arkin and others were able to develop antibody fragment-based inhibitors to regulate specific protein-protein interactions.
As the "modulation" of PPIs not only includes the inhibition, but also the stabilization of quaternary protein complexes, molecules with this mechanism of action (so called molecular glues) are also intensively studied.
Examples
* Tirobifan, inhibitor of the glycoprotein IIb/IIIa, used as a cardiovascular drug
* Maraviroc
Maraviroc, sold under the brand names Selzentry (US) and Celsentri (EU), is an antiretroviral medication used to treat HIV infection. It is taken by mouth. It is in the CCR5 receptor antagonist class.
It was approved for medical use in the Un ...
, inhibitor of the CCR5-gp120 interaction, used as anti-HIV drug.
* AMG-176, AZD5991, S64315, inhibitors of myeloid cell leukemia 1 (Mcl-1) protein and its interactions
See also
* Glycan-protein interactions
* 3did
*Allostery
In the fields of biochemistry and pharmacology an allosteric regulator (or allosteric modulator) is a substance that binds to a site on an enzyme or Receptor (biochemistry), receptor distinct from the active site, resulting in a conformational ...
*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 typ ...
*Biological machine
Molecular machines are a class of molecules typically described as an assembly of a discrete number of molecular components intended to produce mechanical movements in response to specific stimuli, mimicking macromolecular devices such as switch ...
s
* DIMA (database)
*Enzyme catalysis
Enzyme catalysis is the increase in the rate of a process by an "enzyme", a biological molecule. Most enzymes are proteins, and most such processes are chemical reactions. Within the enzyme, generally catalysis occurs at a localized site, calle ...
* HitPredict
* Human interactome
* IsoBase
*Multiprotein complex
A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multidomain enzymes, in which multiple catalytic domains are found in a single polypeptide chain.
Protein c ...
* Protein domain dynamics
* Protein flexibility
*Protein structure
Protein structure is the three-dimensional arrangement of atoms in an amino acid-chain molecule. Proteins are polymers specifically polypeptides formed from sequences of amino acids, which are the monomers of the polymer. A single amino acid ...
*Protein–protein interaction prediction Protein–protein interaction prediction is a field combining bioinformatics and structural biology in an attempt to identify and catalog physical interactions between pairs or groups of proteins. Understanding protein–protein interactions is impo ...
* Protein–protein interaction screening
*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 system ...
References
Further reading
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External links
Protein–Protein Interaction Databases
Library of Modulators of Protein–Protein Interactions (PPI)
{{DEFAULTSORT:Protein-Protein Interaction
Proteomics
Signal transduction
Biophysics
Biochemistry methods
Biotechnology
Quantum biochemistry
Protein–protein interaction assays
Protein complexes