Proteins are large
organic compounds made of amino acids arranged in a linear chain and joined together by peptide bonds between the carboxyland aminogroups of adjacent amino acid residues. The sequence of amino acids in a protein is defined by a geneand encoded in the genetic code. Although this genetic code specifies 20 "standard" amino acids plus selenocysteineand - in certain archaea- pyrrolysine, the residues in a protein are sometimes chemically altered in post-translational modification. This can happen either before the protein is used in the cell, or as part of control mechanisms. Proteins can also work together to achieve a particular function, and they often associate to form stable complexes. [cite book
last = Maton
first = Anthea
coauthors = Jean Hopkins, Charles William McLaughlin, Susan Johnson, Maryanna Quon Warner, David LaHart, Jill D. Wright
title = Human Biology and Health
publisher = Prentice Hall
date = 1993
location = Englewood Cliffs, New Jersey, USA
isbn = 0-13-981176-1
oclc = 32308337]
Like other biological
macromoleculessuch as polysaccharides and nucleic acids, proteins are essential parts of organisms and participate in every process within cells. Many proteins are enzymes that catalyze biochemical reactions and are vital to metabolism. Proteins also have structural or mechanical functions, such as actinand myosinin muscle and the proteins in the cytoskeleton, which form a system of scaffoldingthat maintains cell shape. Other proteins are important in cell signaling, immune responses, cell adhesion, and the cell cycle. Proteins are also necessary in animals' diets, since animals cannot synthesize all the amino acids they need and must obtain essential amino acids from food. Through the process of digestion, animals break down ingested protein into free amino acids that are then used in metabolism.
The word "protein" comes from the Greek word "πρώτειος" ("proteios") "primary". Proteins were first described and named by the Swedish chemist
Jöns Jakob Berzeliusin 1838. However, the central role of proteins in living organisms was not fully appreciated until 1926, when James B. Sumnershowed that the enzyme ureasewas a protein. [cite journal |author=Sumner, JB |title=The Isolation and Crystallization of the Enzyme Urease. Preliminary Paper |url=http://www.jbc.org/cgi/reprint/69/2/435.pdf?ijkey=028d5e540dab50accbf86e01be08db51ef49008f |journal=J Biol Chem |volume=69 |issue= |pages=435–41 |year=1926] The first protein to be sequenced was insulin, by Frederick Sanger, who won the Nobel Prize for this achievement in 1958. The first protein structures to be solved included hemoglobinand myoglobin, by Max Perutzand Sir John Cowdery Kendrew, respectively, in 1958. [cite journal |author=Muirhead H, Perutz M |title=Structure of hemoglobin. A three-dimensional fourier synthesis of reduced human hemoglobin at 5.5 A resolution |journal=Nature |volume=199 |issue=4894 |pages=633–8 |year=1963 |pmid=14074546 |doi=10.1038/199633a0] [cite journal |author=Kendrew J, Bodo G, Dintzis H, Parrish R, Wyckoff H, Phillips D |title=A three-dimensional model of the myoglobin molecule obtained by x-ray analysis |journal=Nature |volume=181 |issue=4610 |pages=662–6 |year=1958 |pmid=13517261 | doi = 10.1038/181662a0 ] The three-dimensional structures of both proteins were first determined by x-ray diffraction analysis; Perutz and Kendrew shared the 1962 Nobel Prize in Chemistryfor these discoveries.
Proteins are linear
polymers built from 20 different L-α- amino acids. All amino acids possess common structural features, including an α carbon to which an aminogroup, a carboxylgroup, and a variable side chainare bonded. Only proline differs from this basic structure as it contains an unusual ring to the N-end amine group, which forces the CO–NH amide moiety into a fixed conformation.Nelson, D. L. and Cox, M. M. (2005) Lehninger's Principles of Biochemistry, 4th Edition, W. H. Freeman and Company, New York.] The side chains of the standard amino acids, detailed in the list of standard amino acids, have different chemical properties that produce three-dimensional protein structure and are therefore critical to protein function. The amino acids in a polypeptide chain are linked by peptide bonds formed in a dehydration reaction. Once linked in the protein chain, an individual amino acid is called a "residue," and the linked series of carbon, nitrogen, and oxygen atoms are known as the "main chain" or "protein backbone." The peptide bond has two resonance forms that contribute some double-bondcharacter and inhibit rotation around its axis, so that the alpha carbons are roughly coplanar. The other two dihedral angles in the peptide bond determine the local shape assumed by the protein backbone.
Due to the chemical structure of the individual amino acids, the protein chain has directionality. The end of the protein with a free carboxyl group is known as the
C-terminusor carboxy terminus, whereas the end with a free amino group is known as the N-terminusor amino terminus.
The words "protein", "
polypeptide," and " peptide" are a little ambiguous and can overlap in meaning. "Protein" is generally used to refer to the complete biological molecule in a stable conformation, whereas "peptide" is generally reserved for a short amino acid oligomers often lacking a stable three-dimensional structure. However, the boundary between the two is not well defined and usually lies near 20–30 residues.Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipurksy SL, Darnell J. (2004). "Molecular Cell Biology" 5th ed. WH Freeman and Company: New York, NY.] "Polypeptide" can refer to any single linear chain of amino acids, usually regardless of length, but often implies an absence of a defined conformation.
Proteins are assembled from amino acids using information encoded in
genes. Each protein has its own unique amino acid sequence that is specified by the nucleotidesequence of the gene encoding this protein. The genetic codeis a set of three-nucleotide sets called codons and each three-nucleotide combination stands for an amino acid, for example AUG stands for methionine. Because DNAcontains four nucleotides, the total number of possible codons is 64; hence, there is some redundancy in the genetic code, with some amino acids specified by more than one codon. Genes encoded in DNA are first transcribed into pre- messenger RNA(mRNA) by proteins such as RNA polymerase. Most organisms then process the pre-mRNA (also known as a "primary transcript") using various forms of post-transcriptional modificationto form the mature mRNA, which is then used as a template for protein synthesis by the ribosome. In prokaryotes the mRNA may either be used as soon as it is produced, or be bound by a ribosome after having moved away from the nucleoid. In contrast, eukaryotes make mRNA in the cell nucleusand then translocate it across the nuclear membraneinto the cytoplasm, where protein synthesis then takes place. The rate of protein synthesis is higher in prokaryotes than eukaryotes and can reach up to 20 amino acids per second.Dobson CM. (2000). The nature and significance of protein folding. In "Mechanisms of Protein Folding" 2nd ed. Ed. RH Pain. "Frontiers in Molecular Biology" series. Oxford University Press: New York, NY.]
The process of synthesizing a protein from an mRNA template is known as translation. The mRNA is loaded onto the ribosome and is read three nucleotides at a time by matching each codon to its
base pairing anticodonlocated on a transfer RNAmolecule, which carries the amino acid corresponding to the codon it recognizes. The enzyme aminoacyl tRNA synthetase"charges" the tRNA molecules with the correct amino acids. The growing polypeptide is often termed the "nascent chain". Proteins are always biosynthesized from N-terminusto C-terminus.
The size of a synthesized protein can be measured by the number of amino acids it contains and by its total
molecular mass, which is normally reported in units of "daltons" (synonymous with atomic mass units), or the derivative unit kilodalton (kDa). Yeastproteins are on average 466 amino acids long and 53 kDa in mass. The largest known proteins are the titins, a component of the muscle sarcomere, with a molecular mass of almost 3,000 kDa and a total length of almost 27,000 amino acids. [cite journal |author=Fulton A, Isaacs W |title=Titin, a huge, elastic sarcomeric protein with a probable role in morphogenesis |journal=Bioessays |volume=13 |issue=4 |pages=157–61 |year=1991 |pmid=1859393 | doi = 10.1002/bies.950130403 ]
Short proteins can also be synthesized chemically by a family of methods known as
peptide synthesis, which rely on organic synthesistechniques such as chemical ligationto produce peptides in high yield. [cite journal |author=Bruckdorfer T, Marder O, Albericio F |title=From production of peptides in milligram amounts for research to multi-tons quantities for drugs of the future |journal=Curr Pharm Biotechnol |volume=5 |issue=1 |pages=29–43 |year=2004 |pmid=14965208 | doi = 10.2174/1389201043489620 ] Chemical synthesis allows for the introduction of non-natural amino acids into polypeptide chains, such as attachment of fluorescentprobes to amino acid side chains. [cite journal |author=Schwarzer D, Cole P |title=Protein semisynthesis and expressed protein ligation: chasing a protein's tail |journal=Curr Opin Chem Biol |volume=9 |issue=6 |pages=561–9 |year=2005 |pmid=16226484 | doi = 10.1016/j.cbpa.2005.09.018 ] These methods are useful in laboratory biochemistryand cell biology, though generally not for commercial applications. Chemical synthesis is inefficient for polypeptides longer than about 300 amino acids, and the synthesized proteins may not readily assume their native tertiary structure. Most chemical synthesis methods proceed from C-terminus to N-terminus, opposite the biological reaction.
Structure of proteins
Most proteins fold into unique 3-dimensional structures. The shape into which a protein naturally folds is known as its
native state. Although many proteins can fold unassisted, simply through the chemical properties of their amino acids, others require the aid of molecular chaperones to fold into their native states. Biochemists often refer to four distinct aspects of a protein's structure:
Primary structure": the amino acid sequence
Secondary structure": regularly repeating local structures stabilized by hydrogen bonds. The most common examples are the alpha helixand beta sheet.Branden C, Tooze J. (1999). "Introduction to Protein Structure" 2nd ed. Garland Publishing: New York, NY] Because secondary structures are local, many regions of different secondary structure can be present in the same protein molecule.
Tertiary structure": the overall shape of a single protein molecule; the spatial relationship of the secondary structures to one another. Tertiary structure is generally stabilized by nonlocal interactions, most commonly the formation of a hydrophobic core, but also through salt bridges, hydrogen bonds, disulfide bonds, and even post-translational modifications. The term "tertiary structure" is often used as synonymous with the term "fold".
Quaternary structure": the shape or structure that results from the interaction of more than one protein molecule, usually called " protein subunits" in this context, which function as part of the larger assembly or protein complex.
cytochrome cin solution show the constantly shifting dynamic structure of the protein. .] Proteins are not entirely rigid molecules. In addition to these levels of structure, proteins may shift between several related structures while they perform their functions. In the context of these functional rearrangements, these tertiary or quaternary structures are usually referred to as "conformations", and transitions between them are called "conformational changes." Such changes are often induced by the binding of a substrate molecule to an enzyme's active site, or the physical region of the protein that participates in chemical catalysis. In solution all proteins also undergo variation in structure through thermal vibration and the collision with other molecules, see the animation on the right.
Proteins can be informally divided into three main classes, which correlate with typical tertiary structures:
globular proteins, fibrous proteins, and membrane proteins. Almost all globular proteins are solubleand many are enzymes. Fibrous proteins are often structural; membrane proteins often serve as receptors or provide channels for polar or charged molecules to pass through the cell membrane.
A special case of intramolecular hydrogen bonds within proteins, poorly shielded from water attack and hence promoting their own
dehydration, are called dehydrons.
Discovering the tertiary structure of a protein, or the quaternary structure of its complexes, can provide important clues about how the protein performs its function. Common experimental methods of structure determination include
X-ray crystallographyand NMR spectroscopy, both of which can produce information at atomic resolution. Cryoelectron microscopyis used to produce lower-resolution structural information about very large protein complexes, including assembled viruses; a variant known as electron crystallographycan also produce high-resolution information in some cases, especially for two-dimensional crystals of membrane proteins. [Gonen T, Cheng Y, Sliz P, Hiroaki Y, Fujiyoshi Y, Harrison SC, Walz T. (2005). Lipid-protein interactions in double-layered two-dimensional AQP0 crystals. "Nature" 438(7068):633–8.] Solved structures are usually deposited in the Protein Data Bank(PDB), a freely available resource from which structural data about thousands of proteins can be obtained in the form of Cartesian coordinatesfor each atom in the protein.
Many more gene sequences are known than protein structures. Further, the set of solved structures is biased toward proteins that can be easily subjected to the conditions required in
X-ray crystallography, one of the major structure determination methods. In particular, globular proteins are comparatively easy to crystallizein preparation for X-ray crystallography. Membrane proteins, by contrast, are difficult to crystallize and are underrepresented in the PDB. [Walian P, Cross TA, Jap BK. (2004). Structural genomics of membrane proteins "Genome Biol" 5(4): 215.] Structural genomicsinitiatives have attempted to remedy these deficiencies by systematically solving representative structures of major fold classes. Protein structure predictionmethods attempt to provide a means of generating a plausible structure for proteins whose structures have not been experimentally determined.
Proteins are the chief actors within the cell, said to be carrying out the duties specified by the information encoded in genes. With the exception of certain types of
RNA, most other biological molecules are relatively inert elements upon which proteins act. Proteins make up half the dry weight of an " Escherichia coli" cell, whereas other macromolecules such as DNA and RNA make up only 3% and 20%, respectively.Voet D, Voet JG. (2004). "Biochemistry" Vol 1 3rd ed. Wiley: Hoboken, NJ.] The set of proteins expressed in a particular cell or cell type is known as its proteome.
The chief characteristic of proteins that allows their diverse set of functions is their ability to bind other molecules specifically and tightly. The region of the protein responsible for binding another molecule is known as the
binding siteand is often a depression or "pocket" on the molecular surface. This binding ability is mediated by the tertiary structure of the protein, which defines the binding site pocket, and by the chemical properties of the surrounding amino acids' side chains. Protein binding can be extraordinarily tight and specific; for example, the ribonuclease inhibitorprotein binds to human angiogeninwith a sub-femtomolar dissociation constant(<10-15 M) but does not bind at all to its amphibian homolog onconase(>1 M). Extremely minor chemical changes such as the addition of a single methyl group to a binding partner can sometimes suffice to nearly eliminate binding; for example, the aminoacyl tRNA synthetasespecific to the amino acid valinediscriminates against the very similar side chain of the amino acid isoleucine.
Proteins can bind to other proteins as well as to small-molecule substrates. When proteins bind specifically to other copies of the same molecule, they can
oligomerize to form fibrils; this process occurs often in structural proteins that consist of globular monomers that self-associate to form rigid fibers. Protein-protein interactions also regulate enzymatic activity, control progression through the cell cycle, and allow the assembly of large protein complexes that carry out many closely related reactions with a common biological function. Proteins can also bind to, or even be integrated into, cell membranes. The ability of binding partners to induce conformational changes in proteins allows the construction of enormously complex signaling networks.
The best-known role of proteins in the cell is as
enzymes, which catalyze chemical reactions. Enzymes are usually highly specific and accelerate only one or a few chemical reactions. Enzymes carry out most of the reactions involved in metabolism, as well as manipulating DNA in processes such as DNA replication, DNA repair, and transcription. Some enzymes act on other proteins to add or remove chemical groups in a process known as post-translational modification. About 4,000 reactions are known to be catalyzed by enzymes. [cite journal|url=http://www.expasy.org/NAR/enz00.pdf|author= Bairoch A.|year= 2000|title= The ENZYME database in 2000 |journal=Nucleic Acids Res|volume=28|pages=304–305|pmid= 10592255 | doi = 10.1093/nar/28.1.304] The rate acceleration conferred by enzymatic catalysis is often enormous - as much as 1017-fold increase in rate over the uncatalyzed reaction in the case of orotate decarboxylase(78 million years without the enzyme, 18 milliseconds with the enzyme). [cite journal |author=Radzicka A, Wolfenden R.|year= 1995|title= A proficient enzyme |journal= Science |volume=6 |issue=267 |pages=90–3| pmid=7809611|doi= 10.1126/science.7809611]
The molecules bound and acted upon by enzymes are called substrates. Although enzymes can consist of hundreds of amino acids, it is usually only a small fraction of the residues that come in contact with the substrate, and an even smaller fraction - 3-4 residues on average - that are directly involved in catalysis. [ [http://www.ebi.ac.uk/thornton-srv/databases/CSA/ The Catalytic Site Atlas at The European Bioinformatics Institute] ] The region of the enzyme that binds the substrate and contains the catalytic residues is known as the
Cell signaling and ligand transport
Many proteins are involved in the process of
cell signalingand signal transduction. Some proteins, such as insulin, are extracellular proteins that transmit a signal from the cell in which they were synthesized to other cells in distant tissues. Others are membrane proteins that act as receptors whose main function is to bind a signaling molecule and induce a biochemical response in the cell. Many receptors have a binding site exposed on the cell surface and an effector domain within the cell, which may have enzymatic activity or may undergo a conformational changedetected by other proteins within the cell. Antibodiesare protein components of adaptive immune systemwhose main function is to bind antigens, or foreign substances in the body, and target them for destruction. Antibodies can be secreted into the extracellular environment or anchored in the membranes of specialized B cells known as plasma cells. Whereas enzymes are limited in their binding affinity for their substrates by the necessity of conducting their reaction, antibodies have no such constraints. An antibody's binding affinity to its target is extraordinarily high.
Many ligand transport proteins bind particular small biomolecules and transport them to other locations in the body of a multicellular organism. These proteins must have a high binding affinity when their
ligandis present in high concentrations, but must also release the ligand when it is present at low concentrations in the target tissues. The canonical example of a ligand-binding protein is haemoglobin, which transports oxygenfrom the lungs to other organs and tissues in all vertebrates and has close homologs in every biological kingdom. Transmembrane proteins can also serve as ligand transport proteins that alter the permeability of the cell membrane to small molecules and ions. The membrane alone has a hydrophobiccore through which polar or charged molecules cannot diffuse. Membrane proteins contain internal channels that allow such molecules to enter and exit the cell. Many ion channelproteins are specialized to select for only a particular ion; for example, potassiumand sodiumchannels often discriminate for only one of the two ions.
Structural proteins confer stiffness and rigidity to otherwise-fluid biological components. Most structural proteins are
fibrous proteins; for example, actinand tubulinare globular and soluble as monomers, but polymerize to form long, stiff fibers that comprise the cytoskeleton, which allows the cell to maintain its shape and size. Collagenand elastinare critical components of connective tissuesuch as cartilage, and keratinis found in hard or filamentous structures such as hair, nails, feathers, hooves, and some animal shells.
Other proteins that serve structural functions are
motor proteins such as myosin, kinesin, and dynein, which are capable of generating mechanical forces. These proteins are crucial for cellular motilityof single celled organisms and the sperm of many sexually reproducing multicellular organisms. They also generate the forces exerted by contracting muscles.
Methods of study
As some of the most commonly studied biological molecules, the activities and structures of proteins are examined both "
in vitro" and " in vivo". "In vitro" studies of purified proteins in controlled environments are useful for learning how a protein carries out its function: for example, enzyme kineticsstudies explore the chemical mechanism of an enzyme's catalytic activity and its relative affinity for various possible substrate molecules. By contrast, "in vivo" experiments on proteins' activities within cells or even within whole organisms can provide complementary information about where a protein functions and how it is regulated.
In order to perform "
in vitro" analysis, a protein must be purified away from other cellular components. This process usually begins with cell lysis, in which a cell's membrane is disrupted and its internal contents released into a solution known as a crude lysate. The resulting mixture can be purified using ultracentrifugation, which fractionates the various cellular components into fractions containing soluble proteins; membrane lipids and proteins; cellular organelles, and nucleic acids. Precipitation by a method known as salting outcan concentrate the proteins from this lysate. Various types of chromatographyare then used to isolate the protein or proteins of interest based on properties such as molecular weight, net charge and binding affinity. The level of purification can be monitored using various types of gel electrophoresisif the desired protein's molecular weight and isoelectric pointare known, by spectroscopyif the protein has distinguishable spectroscopic features, or by enzyme assays if the protein has enzymatic activity. Additionally, proteins can be isolated according their charge [ [http://isoelectric.ovh.org Calculating protein charge (isoelectric point)] ] using electrofocusing.
For natural proteins, a series of purification steps may be necessary to obtain protein sufficiently pure for laboratory applications. To simplify this process,
genetic engineeringis often used to add chemical features to proteins that make them easier to purify without affecting their structure or activity. Here, a "tag" consisting of a specific amino acid sequence, often a series of histidineresidues (a " His-tag"), is attached to one terminus of the protein. As a result, when the lysate is passed over a chromatography column containing nickel, the histidine residues ligate the nickel and attach to the column while the untagged components of the lysate pass unimpeded.
The study of proteins "in vivo" is often concerned with the synthesis and localization of the protein within the cell. Although many intracellular proteins are synthesized in the
cytoplasmand membrane-bound or secreted proteins in the endoplasmic reticulum, the specifics of how proteins are targeted to specific organelles or cellular structures is often unclear. A useful technique for assessing cellular localization uses genetic engineering to express in a cell a fusion proteinor chimera consisting of the natural protein of interest linked to a "reporter" such as green fluorescent protein(GFP). The fused protein's position within the cell can be cleanly and efficiently visualized using microscopy, as shown in the figure opposite. In these cases, additional fluorescent chimeric proteins are generally required to prove the inferred localization.
Other methods for elucidating the cellular location of proteins requires the use of known compartmental markers for regions such as the ER, the Golgi, lysosomes/vacuoles, mitochondria, chloroplasts, plasma membrane, etc. With the use of fluorescently-tagged versions of these markers or of antibodies to known markers, it becomes much simpler to identify the localization of a protein of interest. For example,
indirect immunofluorescencewill allow for fluorescence colocalization and demonstration of location. Fluorescent dyes are used to label cellular compartments for a similar purpose.
Other possibilities exist, as well. For example,
immunohistochemistryusually utilizes an antibody to one or more proteins of interest that are conjugated to enzymes yielding either luminescent or chromogenic signals that can be compared between samples, allowing for localization information.
Another applicable technique is cofractionation in sucrose (or other material) gradients using
isopycnic centrifugation. While this technique does not prove colocalization of a compartment of known density and the protein of interest, it does increase the likelihood, and is more amenable to large-scale studies.
Finally, the gold-standard method of cellular localization is
immunoelectron microscopy. This technique also uses an antibody to the protein of interest, along with classical electron microscopy techniques. The sample is prepared for normal electron microscopic examination, and then treated with an antibody to the protein of interest that is conjugated to an extremely electro-dense material, usually gold. This allows for the localization of both ultrastructural details as well as the protein of interest.
Through another genetic engineering application known as
site-directed mutagenesis, researchers can alter the protein sequence and hence its structure, cellular localization, and susceptibility to regulation, which can be followed "in vivo" by GFP tagging or "in vitro" by enzyme kineticsand binding studies.
Proteomics and bioinformatics
The total complement of proteins present at a time in a cell or cell type is known as its
proteome, and the study of such large-scale data sets defines the field of proteomics, named by analogy to the related field of genomics. Key experimental techniques in proteomics include 2D electrophoresis, which allows the separation of a large number of proteins, mass spectrometry, which allows rapid high-throughput identification of proteins and sequencing of peptides (most often after in-gel digestion), protein microarrays, which allow the detection of the relative levels of a large number of proteins present in a cell, and two-hybrid screening, which allows the systematic exploration of protein-protein interactions. The total complement of biologically possible such interactions is known as the interactome. A systematic attempt to determine the structures of proteins representing every possible fold is known as structural genomics.
The large amount of genomic and proteomic data available for a variety of organisms, including the
human genome, allows researchers to efficiently identify homologous proteins in distantly related organisms by sequence alignment. Sequence profiling tools can perform more specific sequence manipulations such as restriction enzymemaps, open reading frameanalyses for nucleotidesequences, and secondary structureprediction. From this data phylogenetic trees can be constructed and evolutionary hypotheses developed using special software like ClustalWregarding the ancestry of modern organisms and the genes they express. The field of bioinformaticsseeks to assemble, annotate, and analyze genomic and proteomic data, applying computational techniques to biological problems such as gene findingand cladistics.
tructure prediction and simulation
Complementary to the field of structural genomics,
protein structure predictionseeks to develop efficient ways to provide plausible models for proteins whose structures have not yet been determined experimentally. The most successful type of structure prediction, known as homology modeling, relies on the existence of a "template" structure with sequence similarity to the protein being modeled; structural genomics' goal is to provide sufficient representation in solved structures to model most of those that remain. Although producing accurate models remains a challenge when only distantly related template structures are available, it has been suggested that sequence alignment is the bottleneck in this process, as quite accurate models can be produced if a "perfect" sequence alignment is known.Zhang Y, Skolnick J. (2005). The protein structure prediction problem could be solved using the current PDB library. "Proc Natl Acad Sci USA" 102(4):1029–34.] Many structure prediction methods have served to inform the emerging field of protein engineering, in which novel protein folds have already been designed.Kuhlman B, Dantas G, Ireton GC, Varani G, Stoddard BL, Baker D. (2003). Design of a novel globular protein fold with atomic-level accuracy. "Science" 302(5649):1364–8.] A more complex computational problem is the prediction of intermolecular interactions, such as in molecular docking and protein-protein interaction prediction.
The processes of protein folding and binding can be simulated using techniques derived from
molecular dynamics, which increasingly take advantage of distributed computingas in the Folding@Homeproject. The folding of small alpha-helical protein domains such as the villinheadpieceZagrovic B, Snow CD, Shirts MR, Pande VS. (2002). Simulation of folding of a small alpha-helical protein in atomistic detail using worldwide-distributed computing. "J Mol Biol" 323(5):927–37.] and the HIVaccessory proteinHerges T, Wenzel W. (2005). In silico folding of a three helix protein and characterization of its free-energy landscape in an all-atom force field. "Phys Rev Let" 94(1):018101.] have been successfully simulated "in silico", and hybrid methods that combine standard molecular dynamics with quantum mechanicscalculations have allowed exploration of the electronic states of rhodopsins.Hoffmann M, Wanko M, Strodel P, Konig PH, Frauenheim T, Schulten K, Thiel W, Tajkhorshid E, Elstner M. (2006). Color tuning in rhodopsins: the mechanism for the spectral shift between bacteriorhodopsin and sensory rhodopsin II. "J Am Chem Soc" 128(33):10808-18. ]
microorganisms and plants can biosynthesize all 20 standard amino acids, while animals, (including humans) must obtain some of the amino acids from the diet. Key enzymes in the biosynthetic pathways that synthesize certain amino acids - such as aspartokinase, which catalyzes the first step in the synthesis of lysine, methionine, and threoninefrom aspartate- are not present in animals. The amino acids that an organism cannot synthesize on its own are referred to as essential amino acids. If amino acids are present in the environment, microorganisms can conserve energy by taking up the amino acids from their surroundings and downregulating their biosynthetic pathways.
In animals, amino acids are obtained through the consumption of foods containing protein. Ingested proteins are broken down through
digestion, which typically involves denaturation of the protein through exposure to acidand hydrolysisby enzymes called proteases. Some ingested amino acids are used for protein biosynthesis, while others are converted to glucosethrough gluconeogenesis, or fed into the citric acid cycle. This use of protein as a fuel is particularly important under starvationconditions as it allows the body's own proteins to be used to support life, particularly those found in muscle. [cite journal |author=Brosnan J |title=Interorgan amino acid transport and its regulation |url=http://jn.nutrition.org/cgi/content/full/133/6/2068S |journal=J Nutr |volume=133 |issue=6 Suppl 1 |pages=2068S–72S |year=2003 |pmid=12771367] Amino acids are also an important dietary source of nitrogen.
Proteins were recognized as a distinct class of biological molecules in the eighteenth century by Antoine Fourcroy and others, distinguished by the molecules' ability to
coagulateor flocculate under treatments with heat or acid. Noted examples at the time included albumin from egg whites, blood, serum albumin, fibrin, and wheat gluten. Dutch chemist Gerhardus Johannes Muldercarried out elemental analysisof common proteins and found that nearly all proteins had the same empirical formula. The term "protein" to describe these molecules was proposed in 1838 by Mulder's associate Jöns Jakob Berzelius. Mulder went on to identify the products of protein degradation such as the amino acid leucinefor which he found a (nearly correct) molecular weight of 131 Da.
The difficulty in purifying proteins in large quantities made them very difficult for early protein biochemists to study. Hence, early studies focused on proteins that could be purified in large quantities, e.g., those of
blood, egg white, various toxins, and digestive/metabolic enzymes obtained from slaughterhouses. In the late 1950s, the Armour Hot Dog Co. purified 1 kg (= one million milligrams) of pure bovine pancreatic ribonuclease Aand made it freely available to scientists around the world. Linus Paulingis credited with the successful prediction of regular protein secondary structures based on hydrogen bonding, an idea first put forth by William Astburyin 1933. Later work by Walter Kauzmannon denaturation, based partly on previous studies by Kaj Linderstrøm-Lang, contributed an understanding of protein foldingand structure mediated by hydrophobic interactions. In 1949 Fred Sangercorrectly determined the amino acid sequence of insulin, thus conclusively demonstrating that proteins consisted of linear polymers of amino acids rather than branched chains, colloids, or cyclols. The first atomic-resolution structures of proteins were solved by X-ray crystallographyin the 1960s and by NMR in the 1980s. As of 2006, the Protein Data Bankhas nearly 40,000 atomic-resolution structures of proteins. In more recent times, cryo-electron microscopyof large macromolecular assemblies and computational protein structure predictionof small protein domains are two methods approaching atomic resolution.
Comparative Toxicogenomics Database
Essential amino acid
List of recombinant proteins
List of proteins
Edible protein per unit area of land
* Software for protein modeling
* [http://www.tjmitchell.com/stuart/dna.html Protein Songs (Stuart Mitchell - DNA Music Project)] , 'When a "tape" of mRNA passes through the "playing head" of a ribosome, the "notes" produced are amino acids and the pieces of music they make up are proteins.'
* [http://www3.interscience.wiley.com/cgi-bin/jhome/36176?CRETRY=1&SRETRY=0 Proteins (the journal)] , also called "Proteins: Structure, Function, and Bioinformatics" and previously "Proteins: Structure, Function, and Genetics" (1986–1995).
Databases and projects
* [http://ctd.mdibl.org/ Comparative Toxicogenomics Database] curates protein-chemical interactions, as well as gene/protein-disease relationships and chemical-disease relationships.
* [http://harvester.fzk.de Bioinformatic Harvester] A Meta search engine (29 databases) for gene and protein information.
* [http://www.rcsb.org The Protein Databank] (see also [http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html PDB Molecule of the Month] , presenting short accounts on selected proteins from the PDB)
* [http://www.proteopedia.org Proteopedia - Life in 3D] : rotatable, zoomable 3D model with wiki annotations for every known protein molecular structure.
* [http://www.expasy.uniprot.org UniProt the Universal Protein Resource]
* [http://www.proteinatlas.org Human Protein Atlas]
* [http://www.ihop-net.org/UniPub/iHOP/ iHOP - Information Hyperlinked over Proteins]
* [http://web.mit.edu/lms/www/ MIT's Laboratory for Protein Molecular Self-Assembly]
* [http://www.ncbi.nlm.nih.gov/sites/entrez?db=protein NCBI Entrez Protein database]
* [http://www.ncbi.nlm.nih.gov/sites/entrez?db=structure NCBI Protein Structure database]
* [http://www.hprd.org/ Human Protein Reference Database]
* [http://www.humanproteinpedia.org/ Human Proteinpedia]
* [http://folding.stanford.edu/ Folding@Home (Stanford University)]
Tutorials and educational websites
* [http://www.biochemweb.org/proteins.shtml Proteins: Biogenesis to Degradation - The Virtual Library of Biochemistry and Cell Biology]
* [http://web.indstate.edu/thcme/mwking/amino-acid-metabolism.html Amino acid metabolism]
* [http://www.ecosci.jp/ec.html Data Book of Molecules] - Home Page for Learning Environmental Chemistry
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