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Biomolecular structure is the intricate folded, three-dimensional shape that is formed by amolecule ofprotein,DNA, orRNA, and that is important to its function. The structure of these molecules may be considered at any of several length scales ranging from the level of individualatoms to the relationships among entireprotein subunits. This useful distinction among scales is often expressed as a decomposition of molecular structure into four levels: primary, secondary, tertiary, and quaternary. The scaffold for this multiscale organization of the molecule arises at the secondary level, where the fundamental structural elements are the molecule's varioushydrogen bonds. This leads to several recognizabledomains ofprotein structure andnucleic acid structure, including such secondary-structure features asalpha helixes andbeta sheets for proteins, andhairpin loops, bulges, and internal loops for nucleic acids.The termsprimary,secondary,tertiary, andquaternary structure were introduced byKaj Ulrik Linderstrøm-Lang in his 1951 Lane Medical Lectures atStanford University.
The primary structure of abiopolymer is the exact specification of its atomic composition and the chemical bonds connecting those atoms (includingstereochemistry). For a typical unbranched, un-crosslinkedbiopolymer (such as amolecule of a typical intracellularprotein, or ofDNA orRNA), the primary structure is equivalent to specifying the sequence of itsmonomeric subunits, such asamino acids ornucleotides.
Theprimary structure of a protein is reported starting from the aminoN-terminus to the carboxylC-terminus, while the primary structure of DNA or RNA molecule is known as thenucleic acid sequence reported from the5' end to the3' end.The nucleic acid sequence refers to the exact sequence of nucleotides that comprise the whole molecule. Often, the primary structure encodessequence motifs that are of functional importance. Some examples of such motifs are: the C/D[1]and H/ACA boxes[2]ofsnoRNAs,LSm binding site found in spliceosomal RNAs such asU1,U2,U4,U5,U6,U12 andU3, theShine-Dalgarno sequence,[3]theKozak consensus sequence[4]and theRNA polymerase III terminator.[5]
Thesecondary structure of a protein is the pattern of hydrogen bonds in a biopolymer. These determine the general three-dimensional form oflocal segments of the biopolymers, but does not describe the global structure of specific atomic positions in three-dimensional space, which are considered to betertiary structure. Secondary structure is formally defined by the hydrogen bonds of the biopolymer, as observed in an atomic-resolution structure. In proteins, the secondary structure is defined by patterns of hydrogen bonds between backbone amine and carboxyl groups (sidechain–mainchain and sidechain–sidechain hydrogen bonds are irrelevant), where theDSSP definition of a hydrogen bond is used.
Thesecondary structure of a nucleic acid is defined by the hydrogen bonding between the nitrogenous bases.
For proteins, however, the hydrogen bonding is correlated with other structural features, which has given rise to less formal definitions of secondary structure. For example, helices can adopt backbonedihedral angles in some regions of theRamachandran plot; thus, a segment of residues with such dihedral angles is often called ahelix, regardless of whether it has the correct hydrogen bonds. Many other less formal definitions have been proposed, often applying concepts from thedifferential geometry of curves, such ascurvature andtorsion. Structural biologists solving a new atomic-resolution structure will sometimes assign its secondary structureby eye and record their assignments in the correspondingProtein Data Bank (PDB) file.
Thesecondary structure of a nucleic acid molecule refers to thebase pairing interactions within one molecule or set of interacting molecules. The secondary structure of biological RNA's can often be uniquely decomposed into stems and loops. Often, these elements or combinations of them can be further classified, e.g.tetraloops,pseudoknots andstem loops. There are many secondary structure elements of functional importance to biological RNA. Famous examples include theRho-independent terminator stem loops and thetransfer RNA (tRNA) cloverleaf. There is a minor industry of researchers attempting to determine the secondary structure of RNA molecules. Approaches include bothexperimental andcomputational methods (see also theList of RNA structure prediction software).
Thetertiary structure of aprotein or any othermacromolecule is its three-dimensional structure, as defined by the atomic coordinates.[6] Proteins and nucleic acids fold into complex three-dimensional structures which result in the molecules' functions. While such structures are diverse and complex, they are often composed of recurring, recognizable tertiary structure motifs and domains that serve as molecular building blocks. Tertiary structure is considered to be largely determined by the biomolecule'sprimary structure (its sequence ofamino acids ornucleotides).
Theprotein quaternary structure[a] refers to the number and arrangement of multiple protein molecules in a multi-subunit complex.
For nucleic acids, the term is less common, but can refer to the higher-level organization of DNA inchromatin,[7] including its interactions withhistones, or to the interactions between separate RNA units in theribosome[8][9] orspliceosome.
Viruses, in general, can be regarded as molecular machines.Bacteriophage T4 is a particularly well studied virus and itsprotein quaternary structure is relatively well defined.[10] A study by Floor (1970)[11] showed that, during thein vivo construction of the virus by specificmorphogenetic proteins, these proteins need to be produced in balanced proportions for proper assembly of the virus to occur. Insufficiency (due tomutation) in the production of one particular morphogenetic protein (e.g. a critical tail fiber protein), can lead to the production of progeny viruses almost all of which have too few of the particular protein component to properly function, i.e. to infect host cells.[11] However, a second mutation that reduces another morphogenetic component (e.g. in the base plate or head of the phage) could in some cases restore a balance such that a higher proportion of the virus particles produced are able to function.[11] Thus it was found that a mutation that reduces expression of one gene, whose product is employed in morphogenesis, may be partially suppressed by a mutation that reduces expression of a second morphogenetic gene resulting in a more balanced production of the virus gene products. The concept that,in vivo, a balanced availability of components is necessary for proper molecular morphogenesis may have general applicability for understanding the assembly of protein molecular machines.
Structure probing is the process by which biochemical techniques are used to determine biomolecular structure.[12] This analysis can be used to define the patterns that can be used to infer the molecular structure, experimental analysis of molecular structure and function, and further understanding on development of smaller molecules for further biological research.[13] Structure probing analysis can be done through many different methods, which include chemical probing, hydroxyl radical probing, nucleotide analog interference mapping (NAIM), and in-line probing.[12]
Protein andnucleic acid structures can be determined using either nuclear magnetic resonance spectroscopy (NMR) orX-ray crystallography or single-particle cryo electron microscopy (cryoEM). The first published reports forDNA (byRosalind Franklin andRaymond Gosling in 1953) of A-DNAX-ray diffraction patterns—and also B-DNA—used analyses based onPatterson function transforms that provided only a limited amount of structural information for oriented fibers of DNA isolated from calfthymus.[14][15] An alternate analysis was then proposed by Wilkins et al. in 1953 for B-DNA X-ray diffraction and scattering patterns of hydrated, bacterial-oriented DNA fibers and trout sperm heads in terms of squares ofBessel functions.[16] Although theB-DNA form' is most common under the conditions found in cells,[17] it is not a well-defined conformation but a family or fuzzy set of DNA conformations that occur at the high hydration levels present in a wide variety of living cells.[18] Their corresponding X-ray diffraction & scattering patterns are characteristic of molecularparacrystals with a significant degree of disorder (over 20%),[19][20] and the structure is not tractable using only the standard analysis.
In contrast, the standard analysis, involving onlyFourier transforms ofBessel functions[21] and DNAmolecular models, is still routinely used to analyze A-DNA and Z-DNA X-ray diffraction patterns.[22]
Biomolecular structure prediction is the prediction of the three-dimensional structure of aprotein from itsamino acid sequence, or of anucleic acid from itsnucleobase (base) sequence. In other words, it is the prediction of secondary and tertiary structure from its primary structure. Structure prediction is the inverse of biomolecular design, as inrational design,protein design,nucleic acid design, andbiomolecular engineering.
Protein structure prediction is one of the most important goals pursued bybioinformatics andtheoretical chemistry. Protein structure prediction is of high importance inmedicine (for example, indrug design) andbiotechnology (for example, in the design of novelenzymes). Every two years, the performance of current methods is assessed in theCritical Assessment of protein Structure Prediction (CASP) experiment.
There has also been a significant amount ofbioinformatics research directed at the RNA structure prediction problem. A common problem for researchers working with RNA is to determine the three-dimensional structure of the molecule given only the nucleic acid sequence. However, in the case of RNA, much of the final structure is determined by thesecondary structure or intra-molecular base-pairing interactions of the molecule. This is shown by the high conservation ofbase pairings across diverse species.
Secondary structure of small nucleic acid molecules is determined largely by strong, local interactions such ashydrogen bonds andbase stacking. Summing the free energy for such interactions, usually using anearest-neighbor method, provides an approximation for the stability of given structure.[23] The most straightforward way to find the lowest free energy structure would be to generate all possible structures and calculate the free energy for them, but the number of possible structures for a sequence increases exponentially with the length of the molecule.[24] For longer molecules, the number of possible secondary structures is vast.[23]
Sequence covariation methods rely on the existence of a data set composed of multiplehomologous RNA sequences with related but dissimilar sequences. These methods analyze the covariation of individual base sites inevolution; maintenance at two widely separated sites of a pair of base-pairingnucleotides indicates the presence of a structurally required hydrogen bond between those positions. The general problem of pseudoknot prediction has been shown to beNP-complete.[25]
Biomolecular design can be considered the inverse of structure prediction. In structure prediction, the structure is determined from a known sequence, whereas, in protein or nucleic acid design, a sequence that will form a desired structure is generated.
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Other biomolecules, such aspolysaccharides,polyphenols andlipids, can also have higher-order structure of biological consequence.
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