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109 Cards in this Set
- Front
- Back
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non-covalent bond
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- weak by nature
- does not involve the sharing of pairs of electrons - critical in maintaining the three-dimensional structure of large molecules - involves more dispersed variations of electromagnetic interactions |
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covalent bond
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- involves the sharing of pairs of electrons between atoms
- the sharing of electrons allows for a stable electronic configuration -250kj/mol |
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Van Der Waals
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- is the sum of the attractive or repulsive forces between molecules
- force between two permanent dipoles - force between a permanent dipole and a corresponding induced dipole - force between two instantaneously induced dipoles (London dispersion force) |
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Protein principles
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- Function depends on structure
- structure depends on sequence and on weak - noncovalent forced -# of protein folding pattersn is large but finite - Structures of glubular proteins are marginally stable - Marginal stability facilitates motion - motion enabled function |
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What stabilizes a high level of protein structure?
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- 2ary, 3ary and 4ary structure of proteins
- formation of H-bonds - Hydrophobic interactions drive protein folding - Ionic interaction usually occur on the protein surface - VDWaals interactions are ubiquitous |
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Electro static interaction
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An interaction between a positively charged amino group and a negatively charged carboxyl group
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where is all the information necessary for folding?
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All of the information necessary for folding the peptide chain into its native structure is contained in the primary amino acid structure of the peptide
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How do proteins recognize and interpret the folding information?
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-Certain loci along the chain may act as nucleation points
- protein chain must avoid local energy minima - chaperones may help |
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Elements of secondary structure
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- all protein structure is based on the amide plane
- resonance stabilization E of the planar structure is 88KJ/mol |
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How is the secondary structure formed?
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- A twist about the C-N bond involves a twist E of 88 JK/mol times the square of the twist angle.
- Rotation can occur about either of the bonds linking the alpha carbon to the ther atoms of the peptide backbone. |
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Consequences of the amide plane
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- 'two degrees of freedom per residue for the peptide chain'
- angle about the C(a)-N bond is denoted phi - angle about the C(a)-C bond is denoted psi - The entire path of the peptide backbone is known if all phi and psi angles are spedivied and some values are more likely than others |
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Steric crowding
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Reason why many possible conformation about in a-Carbon between two peptide planes are forbidden.
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Ramachandran
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The sterically favorable combinations are the basis for preferred secondary structures.
phi 0, psi 180 = unfavorable phi 180, psi 0 = unfavorable phi 0, psi 0 = unfavorable |
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classes of secondary structure
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alpha helices
other helices beta sheets (composed of beta strands) tight turns (aka beta turns or bends) beta bulge |
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Induced fit model - strain energy
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a continuous change in the conformation and shape of an enzyme in response to substrate binding
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Determinining 3D structure
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- allowable bond angles.
- Interaction between components of the macromolecule . - Interaction between solvent and components. |
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Intramolecular force
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H-bonding: a helix, Bsheet, DNA
Ionic: opposite charged protein Van der waals: weak and short range forces complementary shapes -> a lot of interaction and strong -proteins interact with with surface of another macromolecule, aggregate and interact thru complimentary hydrophobic regions on surface - regions removed from contact with solvent |
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Intermolecular force
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solvation: attraction between component and solvent
Hydrophobic interaction: solute-solute interaction Inability to interact with solvent -> stick together Nucleotide bases: weak interactions, stack one on top of another. Protein: ring stacking (phe), nonpolar aa-cluster memgranes, viruses, chromosomes. |
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dipole-dipole or van der waals forces
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-interaction between permanent dipoles
-Dipole-induced interaction -London dispersion forces - hydrogen bonding 12-30kj/mol |
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enantioselectivity
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the degree to which one enantiomer of a chiral product is preferentially produced in a chemical reaction
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electrostatic stabilization
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Colloidal particles often carry an electrical charge and therefore attract or repel each other. The charge of both the continuous and the dispersed phase, as well as the mobility of the phases are factors affecting this interaction
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hydrophobic interaction
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- Dispersion of lipids in water
- Clusters of lipid molecules - Micelles |
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Dispersion of lipids in water
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Each lipid molecule forces surrounding water molecules to become highly ordered
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Clusters of lipid molecules
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Only lipid portions at the edge of the cluster force the ordering of water. Fewer water molecules are ordered and entropy is increased
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Micelles
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All hydrophobic groups are sequestered from water, no highly ordered shell of water molecules is present and entropy is increased.
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enzyme - example
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albonucleases
trypsin phosphofructokinase alcohol dehydrogenase catalase |
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regulatory protein- example
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insulin
somatotropin thyrotropin lac repressor trp repressor |
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transport protein example
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hemoglobin
serum albumin glucose transporter |
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storage protein - example
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ovalbumin
casein phassolin ferritin |
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contractile and motile protein - example
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acting
myosin tubulin kinesin |
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structural protein - example
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alpha - keratin
collagen elastin fibroin proteoglycans |
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protective proteins - example
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immunoglobulins
thombin fibrinogen ricin |
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exotic proteins - example
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antifreeze protein
monellin resillin glue protein |
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Structure sequence
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primary - amino acids
Secondary - A helix Tertriary - polypeptide chain Quaternary - Amino acid subunit |
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Linus Pauling and Robert corey
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First proposers of an alpha helix
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Max Perutz
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Identified the alpha helix in keratin
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Alpha Helix
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- ubiquitous component of protein
- Stabilized by H-bonds -3.6 residues per turn - It contains 13 atoms if the backbone is closed by a H-bond - phi=-60 degrees and psi=-45degrees |
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Net dipole moment
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the arrangements of N-H and C=O groups (ea. with an individual dipole moment) along the helix axis creates a large net dipole moment
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Helix Capping
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The formation of H- bonds with other nearby donor and acceptor groups 4 N-H at the N-terminus and 4 C-H at the C-terminus lack H partners
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B-pleated sheet
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composed of B-strands, can be parallel or antiparallel, may be pictured as a helix with 2 residues per turn.
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Spider Web Silks
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Have and helix and beta sheets radial strands have increased perdentage of beta sheets that are strong and rigid. The circumferential strands (captures silk) must be flexible and have high percentage of alpha helices
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The B-turn
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(B-bend/tight turn) Allow a peptide to change direction, prevalent are proline and glycine there are 2 forms with 4 residues each
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3D-Structure folding
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- 2ry structures form whenever possible (because of high H-bonds)
- Helices and sheets often pack together - peptides between 2ry structures are short and direct. - They fold to form the most stable structure |
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where does 3D structure stability comes from?
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- Formation of large numbers of intra-molecular hydrogen bonds.
- Reduction in the surface area accessible to solvent that occurs upon folding. |
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Main factors of 3D structure folding
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- Proteins are typically a mixture of hydrophilic and hydrophobic amino acids
- The hydrophobic groups tend to cluster together in the folded interior of the protein |
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Fibrous proteins
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- Most of the polypeptide is arranged parallel to a single axis.
- often mechanically strong - usually insoluble - Play a structural role in nature |
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Types of fibrous proteins
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A-keratin,
B-keratin collagen |
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Alpha keratin
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-found in hair, fingernails, claws, horns, beaks with 311-314 a-helical rods capped with non-helical N & C termini.
- 1st structure=7 residues A-G where A and D are non-polar - Promotes the association of helices to form coiled coils |
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Super helix
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A coiled coil with L-handed twists and reduced the residue numbers to 3.5 so that side chains respeat every 7 residues
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B-Keratin
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- Form extensive B-sheets that extend alternatively above and below the plane placing glycines on one side and alanines/serines on the other, allowing the mesh with the same residue of an adjacent sheet
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Where is beta keratin found?
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silk fibers and bird feathers
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Collagen
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- Principal component of connective tissue (tendon, cartilage, bones)
- Tropocollagen is the basic unit - Has 3 intertwined polypeptide chains of 1 thou residues each. MW=285,000, 300nm long, 1.4 diameter - Has at least 1 residue (Gly) - Unsuited for A and B sheets - Suitable only for triple helix - More extended that an A helix and long strectches of gly,pro-pro/hypro |
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Collagen amino acid composition
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- Amino acid composition includes: 5 hydroxylysine and 3/4 hydroxyproline, that later is formed by vitamin C dependent prolylhydroxilase reaction
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Triple Helix
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- 3 intertwined helical strands poly (gly-pro, pro)
- R-handed triple helix composed of 3 L-handed helical chains. |
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collagen fibers
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- Staggered arrays of tropocollagens of 300nm long w/40nm gaps called "hole regions" that contain carbohydrate and are thought to be nucleation sites for bone formation.
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"hole regions"
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40nm gaps - they contain carbohydrate and are thought to be nucleation sites for bone formation
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collagen triple helix structure
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- Only Gly fits in every 3rd residue that faces the crowded center
- Pro and Hyp suit the constraints of phi and psi - Interchain H-bonds involving Hyp stabilize helix - Strong fibrils |
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How are Fibrils strengthen?
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By intrachain lysine-lysine and interchain hydroxypyridium crosslinks
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Globular proteins
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- More numerous than fibrous proteins
- Their diversity in protein structure reflects the variety of functions performed. - |
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Where does the functional diversity of globular proteins come from?
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- The large number of folded structures that polypeptides can adopt
- the varied chemistry of the side chains of the 20 amino acids |
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Globular proteins design principles
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- It has helices and sheets at its core
- Most polar residues face the outside of the protein & interact with solvent - Hydrophobic residues face the interior of the protein and interact with each other. - Packing of residues is close |
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Small cavities of the globular proteins
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- Empty space formed in the packing of residues of globular proteins with a total volume of 0.72 to 0.77
- provide flexiblity for proteins and formation changes and protein dynamics. - similar tothose of a collection of solid spheres - occupies 25% of the total volume |
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Why does the protein core consist primarily of A-helices and B-sheets?
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- The protein core is predominantly hydrophobic
- The higly polar N-H and C=O moieties of the peptide backbone must be neutralized in the hydrophobic core - The extensively H-bonded nature of A helix and B-sheet is ideal for this purpose |
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Protein core vs. protein surface
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- Core: The helices and sheets are typically constant and conserved in sequence and structure
- Surface: composed of loops and tight turns that connect the helices and sheets of the core. different structural elements that can interact with small molecules or w/other proteins and are the basis for enzyme-substrate interaction, cell signaling and immune responses |
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Random coils
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segments of a protein that are not helices or sheets, usually organized and stable without a recurring pattern.
Strongly influenced by side-chain interations w/the rest of the protein |
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water interaction with globular protein surface
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- includes water molecues
- polar backbone and side chain groups make H-bonds w/solvent water - A-helices are amphiphilic revealing a helical wheel - Some are yrphopic and bureied in the protein interior - Some are polar and entirely solvent-exposed |
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Protetin domain
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- Large globular protein are made up of two or more recognizable and distict structures called domain or modules
- They are compact, folded, usually stable by themselves in aqueous solution. - May consist of single continuous portion of the protein sequence - Can be interrupted by a sequence belonging to another part of the protein |
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Multidomains
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- Are the sum of the functional proterties and behaviors of their constituent domains
- Evolved by the fusion of genes that once coded for separate proteins - 90% of them have been duplicated in other proteins - Many even contain multiple copies of the same domain |
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Protein sectors
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- Evolutionary units of 3D structure
- Quasi-indep. groups of correlated amino acids - Are physically connected in the tertiary structure and ea. has a distinct role - Ea. constitutes an independent mode of sequence divergence in the protein family - Its existence and behavior reflects the evolutionary histories of proteins. |
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How can proteins be denatured?
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- By high concentration of guanidine-HCL or urea.
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Ribonuclease
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- Can be unfolded by treatment with urea.
- B-mercaptoethanol (MCE) cleaves disulfice bonds |
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Is there a single mechanism for protein folding?
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- NO. They fold via specific folding pathways.
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What forces drive folding of globular proteins
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The polypeptide chain must:
- satisfy the constraints of its own structure - fodl so as to "bury" the hydrophobic side chains, minimizing their contact with water - composed of L-amino acids, have a tendency to undergo a "right handed twist" |
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Sequence of events in protein folding.
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- Secondary structures first
- Hydrophobic collapse - Secondary structure interaction - Molten glubules (intermediate, transition states) |
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Hydrophobic collapse
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occurs during folding process of globular proteins that contain a hydrophobic core of nonpolar amino acid side chains, leaving most of the polar or charged residues on the solvent-exposed protein surface
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molten globules
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protein folding intermediates corresponding to the narrowing region of the folding funnel, higher in energy than the native state but lower than the denatured state.
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Funnel of free energies
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- a model for the steps involved in the folding of globular proteins.
- rim= unfolded states, as polpeptides fall down the funnel the energies are lowered as they fold |
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Thermodynamic driving force for folding of globular proteins
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- separate the enthalpy and entropy
- distinguish polar and non-polar groups *- Interaction of nonpolar residues with the solvent nonpolar residues force order on the solvent in the unfolded state. large entropy is increased for the liberated solvent molecules of nonpolar residues inside the protein structure. |
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Why are tertiary proteins only marginally stable?
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because flexibility and motion are important to protein functions
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Importance of globular protein motion
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- Proteins oscillate and fluctuare continuously
- Flexibility is essential for ligand binding, enzyme catalysis and enzyme regulation |
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Proline and motion
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Its cis/trans isomerizations, often occurring over relatively long time scales can alter protein structure significantly
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Folding patters of globular proteins
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- They adopt the most stable tertiary structure by:
---satisfying the constraints inherent in its structure ---fold so as to bury hydrophobic side chains - Polypeptide chains twist slightly in a right handed direction - Ex: right handed twist in B-sheets and crossovers in parallel B-sheets |
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Natural right handed twist of polypeptide chains
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Twists
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Parallel Crossovers
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crossovers
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Antiparallel hairpin
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antiparallel hairpin
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Metamorphic proteins
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- product of dynamism and marginal stability
- one or few mutations can dramatically change a protein's structure |
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Layer structures in globular proteins
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- Layers are found in the structure of protein due to hydrophobic burying
- Consist of layers of backbone and a hydrophobic core - More than half have 2 backbones and 1 core - 1/3 have 3 layers with 2 cores - Few 4 layer structures - One 5 layer structure |
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Structural classes of globular protein (4)
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- According to type and arrangement of 2ry structure
--- All A protein, in which A helices predominate (Human Growth Hormone) --- All B protein, in which B sheets predominate (Manose-specific agglutinia) --- A/B protein, in which helices and sheets are intermingles (porcine ribonuclease inhibitor) --- A+B protein, which contain separate A-helical and b-sheet domains (Ribonuclease H) |
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Role of chaperones
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To protect nascent proteins from the concentrated protein matrix in the cell and perhaps to accelerate slow steps
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IUP
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Intrinsically Unstructured proteins
- Do not possess uniform structural properties but are still essential for cell function - characterized by nearly complete lack of structure and high flexibility - Adopt well-defined structures in comples w/their target protein - characterized by an abundance of polar residues and lack of hydrophobic residues - Contact their target protein over a large surface area |
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A1 - Antitrypsin
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- blocks elastase in the lungs
- Functions as a molecular mousetrpa, binding elastase and dragging it to the other side where is inactivaded and degraded |
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Defects in A1 Antitrypsin
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Can result in lung and liver damage
Genetic variants are often inactive |
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A1 Antirypsin and smoking
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In smoker, oxidation of a crucial met in the flexible loop also inactivates A1 antitrypsin, leading to emphysema
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Diseases of protein folding
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- Linked to abnormalities of protein folding
- Protein misfolding may cause disease by a variety of mechanisms - misfolding may result in loss of function and the onset of disease |
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B-Amyloid peptide
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Causes Alzheimer's disease. Misfolded B-amyloid peptide accumulates in human neural tissue, forming deposits known as neuritic plaques
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Transthyretin
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Familial amyloidotic polyneuropathy - Aggregation of unfolded proteins. Nerves and other organs are damaged by deposits of insoluble protein products.
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p53
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Cancer. It prevents cell with damaged DNA from dividing. One class of p53 mutations leads to misfolding; the misfolded protein is unstable and is destroyed.
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Prion
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creutsfeldt-jakob disease (human equiv. of mad cow disease). With an altered conformation (PrPsc) may seed conformational transitions in normal (PrPc) molecules.
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A1-antitrypsin
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Hereditary emphysema. Mutated forms of this protein fold slowly allowing its target, elastase, to destroy lung tissue
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CFTR (cystic fibrosis transmembrane conductance regulator)
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Cystic fibrosis. Folding intermediates of mutant CFTR forms don't dissociate freely from chaperones, preventing the CFTR from reaching its destination in the membrane.
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Forces driving quaternary association
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- Kd for two subunits: 10-8 to 10-16 M which are the values corresponding to energies of 50-100kJ/mol at 37C
- Entropy loss due to association - unfavorable - Entropy gain due to hydrophobic burying - very favorable - Proteins with two or four subunits predominate in nature |
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Quaternary Level of Structure
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Isologous
heterologous |
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Isologous association
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Two subunits
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Heterologous association
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3 subunits
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Heterologous Tetramer
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4 subunits
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Isologous tetramer
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4 units
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tetramer
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Two sets of isologous protein interactions
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Multimeric proteins
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symmetric arrangements of asymmetric objects
- dimer - pentamer - trimer - hexamer (cyclic) - tetramer - trimer of dimer |
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Structural and Functional Advantages Driving Quaternary Association
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- Stability: reduction of surface to volume ratio
- Genetic economy and efficiency - Bringing catalytic sites together - Cooperativity |
