Wikipedia

Biomolecular structure

Biomolecular structureis the intricate folded, three-dimensional shape that is formed by amoleculeofprotein,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 individualatomsto 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 recognizabledomainsofprotein structureandnucleic acid structure,including such secondary-structure features asalpha helixesandbeta sheetsfor proteins, andhairpin loops,bulges, and internal loops for nucleic acids. The termsprimary,secondary,tertiary,andquaternary structurewere introduced byKaj Ulrik Linderstrøm-Langin his 1951 Lane Medical Lectures atStanford University.

Protein primary structureProtein secondary structureProtein tertiary structureProtein quaternary structure
The image above contains clickable links
The image above contains clickable links
This diagram(which is interactive) ofprotein structureusesPCNAas an example. (PDB:1AXC​)
Nucleic acid primary structureNucleic acid secondary structureNucleic acid tertiary structureNucleic acid quaternary structure
The image above contains clickable links
The image above contains clickable links
Interactive imageofnucleic acid structure(primary, secondary, tertiary, and quaternary) usingDNA helicesand examples from theVS ribozymeandtelomeraseandnucleosome.(PDB:ADNA,1BNA,4OCB,4R4V,1YMO,1EQZ​)

Primary structure

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Main articles:Protein primary structureandNucleic acid sequence

The primary structure of abiopolymeris the exact specification of its atomic composition and the chemical bonds connecting those atoms (includingstereochemistry). For a typical unbranched, un-crosslinkedbiopolymer(such as amoleculeof a typical intracellularprotein,or ofDNAorRNA), the primary structure is equivalent to specifying the sequence of itsmonomericsubunits, such asamino acidsornucleotides.

Theprimary structure of a proteinis reported starting from the aminoN-terminusto the carboxylC-terminus,while the primary structure of DNA or RNA molecule is known as thenucleic acid sequencereported from the5' endto the3' end. The nucleic acid sequence refers to the exact sequence of nucleotides that comprise the whole molecule. Often, the primary structure encodessequence motifsthat are of functional importance. Some examples of such motifs are: the C/D[1] and H/ACA boxes[2] ofsnoRNAs,LSmbinding site found in spliceosomal RNAs such asU1,U2,U4,U5,U6,U12andU3,theShine-Dalgarno sequence,[3] theKozak consensus sequence[4] and theRNA polymerase III terminator.[5]

Secondary structure

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Further information:Protein secondary structureandNucleic acid secondary structure
Secondary (inset) and tertiary structure of tRNA demonstrating coaxial stackingPDB:6TNA​)

Thesecondary structure of a proteinis the pattern of hydrogen bonds in a biopolymer. These determine the general three-dimensional form oflocal segmentsof 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 theDSSPdefinition of a hydrogen bond is used.

Thesecondary structure of a nucleic acidis 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 anglesin 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 geometryof curves, such ascurvatureandtorsion.Structural biologists solving a new atomic-resolution structure will sometimes assign its secondary structureby eyeand record their assignments in the correspondingProtein Data Bank(PDB) file.

Thesecondary structure of a nucleic acidmolecule refers to thebase pairinginteractions 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,pseudoknotsandstem loops.There are many secondary structure elements of functional importance to biological RNA. Famous examples include theRho-independent terminatorstem loops and thetransfer RNA(tRNA) cloverleaf. There is a minor industry of researchers attempting to determine the secondary structure of RNA molecules. Approaches include bothexperimentalandcomputationalmethods (see also theList of RNA structure prediction software).

Tertiary structure

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Further information:Protein tertiary structure,Nucleic acid tertiary structure,andStructural alignment

Thetertiary structureof aproteinor any othermacromoleculeis 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 acidsornucleotides).

Quaternary structure

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Further information:Protein quaternary structureandNucleic acid quaternary structure

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 T4is a particularly well studied virus and itsprotein quaternary structureis relatively well defined.[10]A study by Floor (1970)[11]showed that, during thein vivoconstruction of the virus by specificmorphogeneticproteins, 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 determination

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Further information:Protein structureandNucleic acid structure determination

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]

Proteinandnucleic acidstructures can be determined using either nuclear magnetic resonance spectroscopy (NMR) orX-ray crystallographyor single-particle cryo electron microscopy (cryoEM). The first published reports forDNA(byRosalind FranklinandRaymond Goslingin 1953) of A-DNAX-ray diffraction patterns—and also B-DNA—used analyses based onPatterson functiontransforms 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 molecularparacrystalswith 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 transformsofBessel functions[21]and DNAmolecular models,is still routinely used to analyze A-DNA and Z-DNA X-ray diffraction patterns.[22]

Structure prediction

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Saccharomyces cerevisiaetRNA-Phe structure space: the energies and structures were calculated using RNAsubopt and the structure distances computed using RNAdistance.
Further information:Protein structure predictionandNucleic acid structure prediction

Biomolecular structure prediction is the prediction of the three-dimensional structure of aproteinfrom itsamino acidsequence, or of anucleic acidfrom 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 bybioinformaticsandtheoretical 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 ofbioinformaticsresearch 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 structureor intra-molecular base-pairing interactions of the molecule. This is shown by the high conservation ofbase pairingsacross diverse species.

Secondary structure of small nucleic acid molecules is determined largely by strong, local interactions such ashydrogen bondsandbase 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 multiplehomologousRNA 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-pairingnucleotidesindicates the presence of a structurally required hydrogen bond between those positions. The general problem of pseudoknot prediction has been shown to beNP-complete.[25]

Design

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Further information:Protein designandNucleic acid design

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.

Other biomolecules

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Further information:Lipid bilayer

Other biomolecules, such aspolysaccharides,polyphenolsandlipids,can also have higher-order structure of biological consequence.

See also

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Notes

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  1. ^Herequaternarymeans "fourth-levelstructure ", not"four-wayinteraction ". Etymologicallyquartaryis correct:quaternaryis derived from Latindistributive numbers,and followsbinaryandternary;whilequartaryis derived from Latinordinal numbers,and followssecondaryandtertiary.However,quaternaryis standard in biology.

References

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  1. ^Samarsky DA, Fournier MJ, Singer RH, Bertrand E (July 1998)."The snoRNA box C/D motif directs nucleolar targeting and also couples snoRNA synthesis and localization".The EMBO Journal.17(13): 3747–57.doi:10.1093/emboj/17.13.3747.PMC1170710.PMID9649444.
  2. ^Ganot P, Caizergues-Ferrer M, Kiss T (April 1997)."The family of box ACA small nucleolar RNAs is defined by an evolutionarily conserved secondary structure and ubiquitous sequence elements essential for RNA accumulation".Genes & Development.11(7): 941–56.doi:10.1101/gad.11.7.941.PMID9106664.
  3. ^Shine J,Dalgarno L(March 1975). "Determinant of cistron specificity in bacterial ribosomes".Nature.254(5495): 34–38.Bibcode:1975Natur.254...34S.doi:10.1038/254034a0.PMID803646.S2CID4162567.
  4. ^Kozak M (October 1987)."An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs".Nucleic Acids Research.15(20): 8125–48.doi:10.1093/nar/15.20.8125.PMC306349.PMID3313277.
  5. ^Bogenhagen DF, Brown DD (April 1981). "Nucleotide sequences in Xenopus 5S DNA required for transcription termination".Cell.24(1): 261–70.doi:10.1016/0092-8674(81)90522-5.PMID6263489.S2CID9982829.
  6. ^IUPAC,Compendium of Chemical Terminology,2nd ed. (the "Gold Book" ) (1997). Online corrected version: (2006–) "tertiary structure".doi:10.1351/goldbook.T06282
  7. ^Sipski ML, Wagner TE (March 1977). "Probing DNA quaternary ordering with circular dichroism spectroscopy: studies of equine sperm chromosomal fibers".Biopolymers.16(3): 573–82.doi:10.1002/bip.1977.360160308.PMID843604.S2CID35930758.
  8. ^Noller HF (1984). "Structure of ribosomal RNA".Annual Review of Biochemistry.53:119–62.doi:10.1146/annurev.bi.53.070184.001003.PMID6206780.
  9. ^Nissen P, Ippolito JA, Ban N, Moore PB, Steitz TA (April 2001)."RNA tertiary interactions in the large ribosomal subunit: the A-minor motif".Proceedings of the National Academy of Sciences of the United States of America.98(9): 4899–903.Bibcode:2001PNAS...98.4899N.doi:10.1073/pnas.081082398.PMC33135.PMID11296253.
  10. ^Leiman PG, Kanamaru S, Mesyanzhinov VV, Arisaka F, Rossmann MG (November 2003)."Structure and morphogenesis of bacteriophage T4".Cell Mol Life Sci.60(11): 2356–70.doi:10.1007/s00018-003-3072-1.PMC11138918.PMID14625682.
  11. ^abcFloor E (February 1970). "Interaction of morphogenetic genes of bacteriophage T4".J Mol Biol.47(3): 293–306.doi:10.1016/0022-2836(70)90303-7.PMID4907266.
  12. ^abTeunissen, A. W. M. (1979).RNA Structure Probing: Biochemical structure analysis of autoimmune-related RNA molecules.pp. 1–27.ISBN978-90-901323-4-1.
  13. ^Pace NR, Thomas BC, Woese CR (1999).Probing RNA Structure, Function, and History by Comparative Analysis.Cold Spring Harbor Laboratory Press. pp. 113–17.ISBN978-0-87969-589-7.
  14. ^Franklin RE,Gosling RG(6 March 1953)."The Structure of Sodium Thymonucleate Fibres (I. The Influence of Water Content, and II. The Cylindrically Symmetrical Patterson Function)"(PDF).Acta Crystallogr.6(8): 673–78.doi:10.1107/s0365110x53001939.
  15. ^Franklin RE, Gosling RG (April 1953). "Molecular configuration in sodium thymonucleate".Nature.171(4356): 740–41.Bibcode:1953Natur.171..740F.doi:10.1038/171740a0.PMID13054694.S2CID4268222.
  16. ^Wilkins MH, Stokes AR, Wilson HR (April 1953). "Molecular structure of deoxypentose nucleic acids".Nature.171(4356): 738–40.Bibcode:1953Natur.171..738W.doi:10.1038/171738a0.PMID13054693.S2CID4280080.
  17. ^Leslie AG, Arnott S, Chandrasekaran R, Ratliff RL (October 1980). "Polymorphism of DNA double helices".Journal of Molecular Biology.143(1): 49–72.doi:10.1016/0022-2836(80)90124-2.PMID7441761.
  18. ^Baianu, I. C. (1980). "Structural Order and Partial Disorder in Biological systems".Bull. Math. Biol.42(1): 137–41.doi:10.1007/BF02462372.S2CID189888972.
  19. ^Hosemann R, Bagchi RN (1962).Direct analysis of diffraction by matter.Amsterdam/New York: North-Holland.
  20. ^Baianu IC (1978). "X-ray scattering by partially disordered membrane systems".Acta Crystallogr. A.34(5): 751–53.Bibcode:1978AcCrA..34..751B.doi:10.1107/s0567739478001540.
  21. ^"Bessel functions and diffraction by helical structures".planetphysics.org.[permanent dead link]
  22. ^"X-Ray Diffraction Patterns of Double-Helical Deoxyribonucleic Acid (DNA) Crystals".planetphysics.org.Archived fromthe originalon 24 July 2009.
  23. ^abMathews DH (June 2006). "Revolutions in RNA secondary structure prediction".Journal of Molecular Biology.359(3): 526–32.doi:10.1016/j.jmb.2006.01.067.PMID16500677.
  24. ^Zuker M, Sankoff D (1984). "RNA secondary structures and their prediction".Bull. Math. Biol.46(4): 591–621.doi:10.1007/BF02459506.S2CID189885784.
  25. ^Lyngsø RB, Pedersen CN (2000). "RNA pseudoknot prediction in energy-based models".Journal of Computational Biology.7(3–4): 409–27.CiteSeerX10.1.1.34.4044.doi:10.1089/106652700750050862.PMID11108471.
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