Protein contact map
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A protein contact map represents the distance between all possible amino acid residue pairs of a three-dimensional
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, the monomers of the polymer. A single amino acid monom ...
using a binary two-dimensional matrix. For two residues i and j, the ij element of the matrix is 1 if the two residues are closer than a predetermined threshold, and 0 otherwise. Various contact definitions have been proposed: The distance between the Cα-Cα atom with threshold 6-12 Å; distance between Cβ-Cβ atoms with threshold 6-12 Å (Cα is used for
Glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid ( carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinog ...
); and distance between the side-chain centers of mass.


Overview

Contact maps provide a more reduced representation of a protein structure than its full 3D atomic coordinates. The advantage is that contact maps are invariant to rotations and translations. They are more easily predicted by
machine learning Machine learning (ML) is a field of inquiry devoted to understanding and building methods that 'learn', that is, methods that leverage data to improve performance on some set of tasks. It is seen as a part of artificial intelligence. Machine ...
methods. It has also been shown that under certain circumstances (e.g. low content of erroneously predicted contacts) it is possible to reconstruct the 3D coordinates of a protein using its contact map. Contact maps are also used for protein
superimposition Superimposition is the placement of one thing over another, typically so that both are still evident. Graphics In graphics, superimposition is the placement of an image or video on top of an already-existing image or video, usually to add to t ...
and to describe similarity between protein structures. They are either predicted from
protein sequence Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthes ...
or calculated from a given structure.


Contact map prediction

With the availability of high numbers of genomic sequences it becomes feasible to analyze such sequences for ''coevolving residues''. The effectiveness of this approach results from the fact that a mutation in position ''i'' of a protein is more likely to be associated with a mutation in position ''j'' than with a back-mutation in ''i'' if both positions are functionally coupled (e.g. by taking part in an enzymatic domain, or by being adjacent in a folded protein, or even by being adjacent in an oligomer of that protein). Several statistical methods exist to extract from a
multiple sequence alignment Multiple sequence alignment (MSA) may refer to the process or the result of sequence alignment of three or more biological sequences, generally protein, DNA, or RNA. In many cases, the input set of query sequences are assumed to have an evolutio ...
such coupled residue pairs: observed versus expected frequencies of residue pairs (OMES); the McLachlan Based Substitution correlation (McBASC); statistical coupling analysis;
Mutual Information In probability theory and information theory, the mutual information (MI) of two random variables is a measure of the mutual dependence between the two variables. More specifically, it quantifies the " amount of information" (in units such ...
(MI) based methods; and recently direct coupling analysis (DCA).
Machine learning Machine learning (ML) is a field of inquiry devoted to understanding and building methods that 'learn', that is, methods that leverage data to improve performance on some set of tasks. It is seen as a part of artificial intelligence. Machine ...
algorithms have been able to enhance MSA analysis methods, especially for non-homologous proteins (ie. shallow MSA's). Predicted contact maps have been used in the prediction of membrane proteins where helix-helix interactions are targeted.


HB Plot

Knowledge of the relationship between a
protein 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, res ...
's structure and its dynamic behavior is essential for understanding protein function. The description of a protein three dimensional structure as a network of
hydrogen bonding In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a l ...
interactions (HB plot) was introduced as a tool for exploring protein structure and function. By analyzing the network of tertiary interactions, the possible spread of information within a protein can be investigated. HB plot offers a simple way of analyzing protein secondary structure and
tertiary structure Protein tertiary structure is the three dimensional shape of a protein. The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures, the protein domains. Amino acid side chains may i ...
. Hydrogen bonds stabilizing secondary structural elements ( secondary hydrogen bonds) and those formed between distant
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
residues - defined as tertiary hydrogen bonds - can be easily distinguished in HB plot, thus, amino acid residues involved in stabilizing
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, the monomers of the polymer. A single amino acid monom ...
and function can be identified.


Features

The plot distinguishes between main chain-main chain, main chain-
side chain In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called the "main chain" or backbone. The side chain is a hydrocarbon branching element of a molecule that is attached to a ...
and side chain-side chain
hydrogen bonding In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a l ...
interactions. Bifurcated hydrogen bonds and multiple hydrogen bonds between
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
residues; and intra- and interchain hydrogen bonds are also indicated on the plots. Three classes of hydrogen bondings are distinguished by color-coding; short (distance smaller than 2.5 Å between donor and acceptor), intermediate (between 2.5 Å and 3.2 Å) and long hydrogen bonds (greater than 3.2 Å).


Secondary structure elements in HB plot

In representations of the HB plot, characteristic patterns of secondary structure elements can be recognised easily, as follows: # Helices can be identified as strips directly adjacent to the diagonal. #Antiparallel beta sheets appear in HB plot as cross-diagonal. #Parallel beta sheets appears in the HB plot as parallel to the diagonal. # Loops appear as breaks in the diagonal between the cross-diagonal
beta-sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a ge ...
motifs.


Examples of usage


Cytochrome P450s

The
cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...
s (P450s) are xenobiotic-metabolizing
membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. ...
-bound
heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consis ...
-containing enzymes that use molecular
oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as ...
and electrons from NADPH cytochrome P450 reductase to oxidize their substrates. CYP2B4, a member of the cytochrome P450 family is the only protein within this family, whose
X-ray structure X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...
in both open 11 and closed form 12 is published. The comparison of the open and closed structures of CYP2B4 structures reveals large-scale conformational rearrangement between the two states, with the greatest conformational change around the residues 215-225, which is widely open in ligand-free state and shut after ligand binding; and the region around loop C near the heme. Examining the HB plot of the closed and open state of CYP2B4 revealed that the rearrangement of tertiary hydrogen bonds was in excellent agreement with the current knowledge of the cytochrome P450
catalytic cycle In chemistry, a catalytic cycle is a multistep reaction mechanism that involves a catalyst. The catalytic cycle is the main method for describing the role of catalysts in biochemistry, organometallic chemistry, bioinorganic chemistry, materials s ...
. The first step in
P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compo ...
catalytic cycle is identified as substrate binding. Preliminary binding of a ligand near to the entrance breaks hydrogen bonds S212-E474, S207-H172 in the open form of CYP2B4 and hydrogen bonds E218-A102, Q215-L51 are formed that fix the entrance in the closed form as the HB plot reveals. The second step is the transfer of the first electron from NADPH via an electron transfer chain. For the electron transfer a conformational change occurs that triggers interaction of the P450 with the NADPH cytochrome P450 reductase. Breaking of hydrogen bonds between S128-N287, S128-T291, L124-N287 and forming S96-R434, A116-R434, R125-I435, D82-R400 at the NADPH cytochrome P450 reductase
binding site In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...
—as seen in HB plot—transform CYP2B4 to a conformation state, where binding of NADPH cytochrome P450 reductase occurs. In the third step, oxygen enters CYP2B4 in the closed state - the state where newly formed hydrogen bonds S176-T300, H172-S304, N167-R308 open a tunnel which is exactly the size and shape of an
oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as ...
molecule.


Lipocalin family

The
lipocalin The lipocalins are a family of proteins which transport small hydrophobic molecules such as steroids, bilins, retinoids, and lipids and most lipocalins are also able to bind to complexed iron (via siderophores or flavonoids) as well as heme. They ...
family is a large and diverse family of proteins with functions as small
hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, t ...
molecule transporters.
Beta-lactoglobulin β-Lactoglobulin (BLG) is the major whey protein of cow and sheep's milk (~3 g/L), and is also present in many other mammalian species; a notable exception being humans. Its structure, properties and biological role have been reviewed many time ...
is a typical member of the lipocalin family. Beta-lactoglobulin was found to have a role in the transport of hydrophobic ligands such as
retinol Retinol, also called vitamin A1, is a fat-soluble vitamin in the vitamin A family found in food and used as a dietary supplement. As a supplement it is used to treat and prevent vitamin A deficiency, especially that which results in xeroph ...
or
fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
s. Its
crystal structure In crystallography, crystal structure is a description of the ordered arrangement of atoms, ions or molecules in a crystalline material. Ordered structures occur from the intrinsic nature of the constituent particles to form symmetric patterns ...
were determined .g. Qin, 1998!-- This is not a proper reference format --> with different ligands and in ligand-free form as well. The crystal structures determined so far reveal that the typical lipocalin contains eight-stranded antiparallel-barrel arranged to form a conical central cavity in which the hydrophobic ligand is bound. The structure of beta-lactoglobulin reveals that the barrel-form structure with the central cavity of the protein has an "entrance" surrounded by five beta-loops with centers around 26, 35, 63, 87, and 111, which undergo a conformational change during the ligand binding and close the cavity. The overall shape of beta-lactoglobulin is characteristic of the lipocalin family. In the absence of
alpha-helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...
, the main diagonal almost disappears and the cross-diagonals representing the
beta-sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a ge ...
s dominate the plot. Relatively low number of tertiary hydrogen bonds can be found in the plot, with three high-density regions, one of which is connected to a loop at the residues around 63, a second is connected to the loop around 87, and a third region which is connected to the regions 26 and 35. The fifth loop around 111 is represented only one tertiary hydrogen bond in the HB plot. In the three-dimensional structure, tertiary hydrogen bonds are formed (1) near to the entrance, directly involved in conformational rearrangement during ligand binding; and (2) at the bottom of the "barrel". HB plots of the open and closed forms of beta-lactoglobulin are very similar, all unique motifs can be recognized in both forms. Difference in HB plots of open and ligand-bound form show few important individual changes in tertiary hydrogen bonding pattern. Especially, the formation of hydrogen bonds between Y20-E157 and S21-H161 in closed form might be crucial in conformational rearrangement. These hydrogen bonds lie at the bottom of the cavity, which suggests that the closure of the entrance of a lipocalin starts when a ligand reached the bottom of the cavity and broke hydrogen bonds R123-Y99, R123-T18, and V41-Q120. Lipocalins are known to have very low sequence similarity with high structural similarity. The only conserved regions are exactly the region around 20 and 160 with an unknown role.


See also

*
Ramachandran plot In biochemistry, a Ramachandran plot (also known as a Rama plot, a Ramachandran diagram or a ,ψplot), originally developed in 1963 by G. N. Ramachandran, C. Ramakrishnan, and V. Sasisekharan, is a way to visualize energetically allowed regions ...
* Structural classification of proteins * CATH * HB plot *
Dot plot (bioinformatics) In bioinformatics a dot plot is a graphical method for comparing two biological sequences and identifying regions of close similarity after sequence alignment. It is a type of recurrence plot. History One way to visualize the similarity between ...
*
Self-similarity matrix In data analysis, the self-similarity matrix is a graphical representation of similarity measure, similar sequences in a data series. Similarity can be explained by different measures, like spatial distance (distance matrix), correlation, or compar ...


References


External links


DISTILL
mdash; prediction of protein structural features (including protein residue contact maps)
Structural Proteomics Tools
— includes amino acid contact maps
ProfCon
— prediction of inter-residue contacts
TMHcon
— prediction of helix-helix contacts specifically within the transmembrane parts of membrane proteins
TMhit
— A new transmembrane helix-helix interaction prediction method based on residue contacts{{dead link, date=July 2017

— A protein contact map prediction server

—A Tool for Protein Contact-Map Visualization in jerseysforcheapshop Proteomics Protein structure