Bioinformatics

Biological Basics

1. Amino acids I 2. Peptide bond I 3. Proteins I 4. DNA I 5. Miscellaneous

3. Proteins

• macromolecules / polymers
• 'workhorses of the cell'
• made up of various L-amino acids connected by peptide bonds
• linear chains (unbranched)
  • protein molecule that consists of a single polypeptide chain is said to be monomeric
  • proteins made up of more than one polypeptide chain are called oligomeric
• interact with other proteins, nucleic acids, small molecules, ions, etc.

Protein Classification

possible in different ways:

chemical composition
homoproteins (simple proteins)	contain exclusively amino acids
heteroproteins (conjugated proteins)	contain additionally a non-protein part, the so-called "prosthetic group" (organic and inorganic groupings) proteins can be further divided in depending on the type of the prosthetic group nucleo-, lipo-, glyco-, phospho-, hemo-, flavo- and metallo- proteins iron, zinc, calcium, molybdenum and copper are the most important metal ions in proteins Classification of conjugated proteins class prosthetic group example glycoprotein saccharide immunoglobulin (antibody) interferon (antiviral agent) hemoprotein heme hemoglobin (O2 carrier in blood) myoglobin (O2 storage in muscle) lipoprotein lipid LDL - low-density lipoprotein (lipid carriers) HDL - high-density lipoprotein (lipid carriers) metalloprotein metal ion Ca2+ in calmodulin (muscle contraction) Fe2+ in hemoglobin/myoglobin Fe2+ in ferritin (Fe2+ storage) Zn2+ in carboxypeptidase (digestive enzyme) nucleoprotein nucleic acid RNA-bound protein (protein synthesis) phosphoprotein phosphate ester casein (milk protein)

amino acid composition

average molecular weight of one amino acid is about 113 g/mol allows calculation, how many amino acid residues are in a protein of a given size most abundant amino acids are leucine, serine, lysine and glutamic acid constitute 32% of amino acids in proteins rare amino acids are cysteine, tryptophan and methionine together 5% of amino acids in proteins

binding

for example: antibodies

cellular structure

structural proteins provide strength to cells for example: fibronectin, collagen, keratin ...

enzymatic catalysis

largest class of proteins (> 3.000 enzymes known) accelerate the rates of various biological reactions that take place in the cell almost every reaction that occurs in biochemistry is facilitated by some sort of enzyme generally highly specific (reaction with only one substrate to form one product) typically named based on the reaction that they catalyze (suffix: -ase) proteases (trypsin, chymotrypsin, carboxypeptidases) lactase (hydrolyze milk sugar)

mechanical support

muscle contraction actin and myosin in muscles of animals molecular machines ... tubulin

regulation

regulatory proteins influence the behaviour or abundance of enzymes (directly or indirectly) regulate cellular processes based on their abilities to bind to other macromolecules, such as receptors, DNA, RNA, etc. well known example: insulin hormone regulates glucose metabolism fairly small protein (5.7 kD) composed of two identical polypeptide chains that are linked via a disulfide bond

storage

storage proteins act as a biological reservior for specific nutrients proteins which store metal ions (positively charged metal ions can bind to negatively charged side chains, or side chains that are very polar) classic example: ferritin binds and stores iron

transport

transport proteins deliver specific substances well known example: hemoglobin, myoglobin many others are membrane bound proteins which aid in shuttling nutrients or metabolites (glucose, vitamins, amino acids) across the cell membrane; ion channels [import of nutrients as well as export of waste]

Mutation
protein function ultimately depends on the primary structure DNA structure of the gene, that directs the protein synthesis, determines the primary structure alteration in gene structure can produce alteration in primary structure (can destroy the function) not all alterations in primary structure brings significant altered function ! substitution of an amino acid with similar size, charge and polarity does not cause much change substitution of an amino acid with very different size, charge and polarity causes large changes in the 3D-structure / function
Example:
sickle cell hemoglobin (sickle cell anemia) normal hemoglobin composed of 4 protein subunits (2 α- and 2 ß-chains) it looks like a round or ball-shaped folded molecule sickle cell hemoglobin valine is substituted for glutamic acid at 6th amino acid of both ß-chains (chemical changes) cause to shape changes and lowered oxygen concentration deoxygenated molecules can link to each other to build a polymer electron micrograph of normal (circular) and sickled red blood cells

small	50 - 150 amino acids
very large	over 1000 amino acids

solubility in water, salt solution or ethanol
	water	salt solutions	ethanolabsolute	70-80% ethanol
Albumins	+	+
Globulins	(+)	+
Histones		+
Prolamines	-		-	+
Scleroproteins	-	-

three-dimensional structure and functional role

membrane proteins

constitute about 25% of all the proteins play critical roles in cellular communication with the outside world and in energy metabolism very little known about membrane protein structure (hard to determine 3D-structure) roles: transport of molecules/ions in or out of cells cell recognition, receptors, cell to cell communication amino acid sidechains of transmembrane segments must be non-polar ( e.g. Ala, Val, Leu, Ile, Phe) helices and ß-barrels peptide bonds participate in hydrogen-bonding with the lipid bilayer

Membrane proteins of known 3D structure (by S. White, Laboratory at UC Irvine)

fibrous proteins (structural and contractile)

typically water-insoluble relatively "hydrophobic" amino acids (e.g. Ala, Val, Leu, Ile, Met, Phe) located both in the interior and exterior protein domains physically tought impart strength and/or elasticity built up from single repeating elements of secondary structure rope-like proteins that provide strength and framework to tissues aggregate tightly into fibers or sheets with strong secondary attractive forces tend to be long, narrow molecules construct macroscopic structures collagen most abundant protein in vertebrates (~ 20 % of all proteins in human body) found in cartilage, tendons, bones, teeth, skin, and blood vessels extremely strong high glycine and proline/hydroxyproline content proline residues convert into hydroxyproline during the synthesis of collagen hydroxylation requires vitamine C high lysine content results in lysinonorleucine cross-links very little amount of cysteine composed of 3 left-handed helices wound into the "collagen triple helix" basic unit = tropocollagen 3 left-handed helices form right-handed triple helix wind around each other to form a superhelical cable no H-bonds within the strands collagen triple helix very unique with Gly-Pro-Pro/HyPro [Gly-X-HydroxyPro] every 3rd residue Gly in the center 3.3 residues/turn extensive H-bonding using carbonyl and amine of Gly results in further strengthening at least 18 different types of collagen; types I - V are the most common Collagen - Protein of the Month (by D.S. Goodsell, PDB) elastin stretchable (rubber band-like), elastic fibrous protein protein of tendons, ligaments and blood vessel walls irregular amino acid structure; contains mostly Gly, Ala and Val with some Lys and Pro random coil structure, little secondary structure (not irregular structure) unique cross-links, called desmosine, made of four Lys connected through their side chains, which gives the elastin strong elastic properties fibroin silk protein form spider webs, cocoon and nests ß-sheet structures with glycine on one hand and alanine/serine on the other contain repeats of [Gly-Ala-Gly-Ala-Gly-Ser-Gly-Ala-Ala-Gly-(Ser-Gly-Ala-Gly-Ala-Gly)8] ß-sheet structures stack on top of each other bulky regions with valine and tyrosine interrupt the ß-sheet and allow the stretchiness   α-keratin [hair, skin, wool, nails, claws, hooves] soft and hard fibrous protein highly insoluble in water composed of right handed α-helices with hydrophobic amino acids coiled-coil structure of two α-helices of about 300 disulfide bonds aid formation of protofilaments (cross-links) coiled-coil structure of two ? helices of about 300 amino acids with hydrophobic amino acids at every fourth or seventh, making a leucine zipper in ? keratins, pairs of coiled-coils are twisted to form the protofibril (4 helices) Eight protofibril from a circular or square microfibril (M 6.11) Packing into coiled conformations at higher level is by disulfide bridges and secondary attractive forces quaternary structure consists of two a-Keratins in parallel that wrap around each other to form a super twisted coiled coil helical of the supertwists is left handed hydrophobic R groups in the 2 helices form hydrophobic interactionsmany coiled coils can be organized into the supramolecular structure of hair S-S bonds between the polypeptide chains of multihelical "ropes" add strength Parry, D.A.; Crewther, W.G.; Fraser, R.D.; MacRae, T.P.; J. Mol. Biol. 1977, 113(2), 449-454. Structure of alpha-keratin: structural implication of the amino acid sequences of the type I and type II chain segments. [PubMed]

globular proteins

they do most of the metabolic work like regulatory, transport, catalysis and protection all enzymes and regulatory proteins are globular typically water-soluble, roughly spherical and tightly folded hydrophilic nature polar residues = on the surface hydrophobic residues = on the interior prosthetic gropus often found in pockets often stable structures more 3D-structure information available for globular proteins than for all other classes of proteins combined show a quite variety of globular protein structures they do not aggregate into macroscopic structures unique, compact tertiary structures use α helices, ß sheets, turns and non-regular structures in a particular arrangement   enzymes trypsin cleaves proteins hormones insulin glucose regulator protection immunoglobulins immune response transporters hemoglobin transferrin oxygen transport iron transport

• LIFE - The Science of Biology (7th edition) (by W.K. Purves, D. Sadava, G.H. Orians, H. Craig Heller)
• Cozzone, A.J.; Encyclopedia of Life Sciences 2002, 1-10. Proteins: fundamental chemical properties. [PDF]

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