What types of bonds stabilize the protein structure

Protein structure

Folding and structure of the 1EFN protein

The Protein structure is divided into different structural levels in biochemistry. The division into a hierarchy of primary structure (amino acid sequence), secondary structure, tertiary structure and quaternary structure was first proposed in 1952 by Kaj Ulrik Linderstrøm-Lang.[1] In relation to the spatial arrangement of a protein, the term protein conformation is used synonymously.[2] Changes in the spatial protein structure are called conformational changes.

The hierarchy of the structural levels

In biochemistry, a distinction is made between four hierarchically arranged structural levels in proteins:

Some proteins also arrange themselves in a “superstructure” or “superstructure” that goes beyond the quaternary structure. This is molecularly just as predetermined as the other structural levels. Examples of suprastructures are collagen in the collagen fibril, actin, myosin and titin in the sarcomere of the muscle fibril, and capsomeres in the capsid of enveloped viruses

Formation of a spatial structure

The process of three-dimensional space filling of a protein takes place partly spontaneously during the translation, partly the cooperation of enzymes or chaperones is necessary. Ligands also influence the protein structure, so that some proteins can adopt different structures depending on their complexation with cofactors or substrates (see: Conformational change). This ability to change the spatial structure is necessary for many enzyme activities.

Disorders in the formation of a functional spatial structure are referred to as protein misfolding diseases. An example of this is Huntington's disease. Diseases that are caused by a malformation of the protein structure are called prion diseases. BSE or Alzheimer's disease are examples of such diseases. Type 2 diabetes mellitus is also a protein misfolding disease, it is based on a misfolding of the amylin.[3]

Structure determination

Various experimental methods are available to elucidate the spatial protein structure:

  • In crystal structure analysis, a diffraction image of a protein crystal is created - mostly using X-rays - from which its three-dimensional structure can then be calculated. The production of the single crystals required for this is very complicated and has not yet been possible for some proteins. Another problem with this method is that the structure of the proteins in the crystal does not necessarily correspond to the natural structure (crystal packing). A minimum size of the protein crystals is required for evaluable diffraction images. In order to obtain the required amount of substance, proteins that were produced by bacteria are often used. These sometimes do not have the post-translational modifications found in proteins of higher organisms.
  • The structure of a protein in solution can be determined by means of NMR spectroscopy, which corresponds more closely to the physiological (“natural”) conditions of the protein. Since atoms of the protein move in this state, there is no clear structure. In order to obtain a "clear" structure, the shown structures are usually averaged. Up to now, NMR spectroscopy cannot be carried out for all types of protein. The size in particular is a limiting factor here. Proteins> 30 kDa cannot yet be analyzed because the NMR results are so complex that no clear protein structure can be derived from them.
  • The structure depends on various physicochemical boundary conditions (such as pH, temperature, salt content, presence of other proteins). The thermal stability can be compared, for example, with the Fastpp proteolysis assay.[4] The Stokes radius of a native protein or a protein complex can be determined via native PAGE, size exclusion chromatography or isopycnic centrifugation. These two methods can be combined with a cross-linking or an alanine scan.

Structure prediction

The prediction of spatial protein structures achieves good results when proteins with a similar sequence and known structure already exist. This enables the so-called homology modeling, whereby the new sequence is mapped onto the sequence, the structure of which is known, and thus “fitted” into the structure. This technique is similar to sequence alignment.

The prediction is more difficult if the structures of similar amino acid sequences are not yet known. The Levinthal paradox shows that the calculation of the energetically most favorable conformation is not feasible due to the many possibilities. In the last few years great advances have been made in bioinformatics and various methods of de novo- or ab initio-Structural prediction developed. However, no reliable method for elucidating the structure of proteins has yet been found.

In order to be able to compare new methods of structural prediction with one another, there has been the CASP competition for several years (critical assessment of techniques for protein structure prediction). In this competition, amino acid sequences of structures that crystallographers are currently working on are made available to the participants. Participants use their own methods to predict the structures. An evaluation team then compares the predictions with the experimentally determined structures.

The structure prediction is also the goal of several projects of distributed computing such as Rosetta @ home, POEM @ home, Predictor @ home, Folding @ home and Human Proteome Folding Project. The game Foldit also makes use of the advantages of crowdsourcing to clarify the structure.

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  1. ↑ Linderstrøm-Lang, K.U. (1952): Proteins and Enzymes. In: Lane Medical Lectures. Vol. 6, pp. 1-115. Stanford University Publications, University Series, Medical Sciences, Stanford University Press.
  2. ↑ Christian B. Anfinsen received the Nobel Prize for Chemistry in 1972 "for his work on ribonuclease, in particular the connection between amino acid series and biologically active conformations" (official reason for the award of the Royal Swedish Academy of Sciences
  3. ↑ L. Skora: High-resolution characterization of structural changes involved in prion diseases and dialysis-related amyloidosis. Dissertation, Georg-August-Universität Göttingen, 2009, p. Iii.
  4. jsessionid = CE17B6912F77B4069E4969431710B8A7? uri = info% 3Adoi% 2F10.1371% 2Fjournal.pone.0046147 & representation = PDF {{{title}}}. .

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