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Protein Structure 2
Biochem and medical genetics
| Question | Answer |
|---|---|
| What are the native states of proteins | Equilibrium states with a rapid exchange between functional and non-functional states. The functional state is not necessary the most stable state, as it must be able to be broken down by the body. |
| What is chemical equilibrium a compromise between | Attractive interactions between residues, ions, cofactors and water A non-stable functional state in some conditions The universe will tend towards disorder- proteins was to unfold Effect of proteins on the solvent Hydrophobic effect- |
| Forces that stabilise the native state | Peptide bond Disulphide bridges Metal ions- commonly bound to cystine and histidine Hydrogen bonds Hydrophobic effect Van de Waals forces Amino acids interact via ionic interactions called salt bridges |
| What are the main electrostatic interactions found in proteins | Charge - Charge (energy of this increases when in lipids e.g. cell membranes) Charge - Dipole Dipole - Dipole These are longer interactions so are used in higher order structure Energy from groups shielded from water is higher (lower e value) |
| What is the equation of interaction | Strength of a bond is given by: E = (q1 x q2) / (eR^n) n = 2 for charge-charge, 4 for charge-dipole and 6 for dipole-dipole e is the dielectric constant |
| Define quaternary structure | The assembly of multiple polypeptide chains into a complete functional protein unit |
| 2 types of quaternary structure | Identical proteins- dimers, trimers etc called homo-oligmers e.g GroEL which helps fold and unfold proteins Non-identical proteins- distinct peptide chains called hetero-oligners whose chains are often joined by disulphide bridges e.g. ATPases |
| What is the Levinthal paradox | Proteins cannot randomly sample the theoretical number of possible conformational states to find the correct, native fold. If each residue had two states, it would have 2^100 possible states. So proteins must have guided folding pathways |
| What neurodegenerative diseases are associated with protein misfolding | Alzheimer's Parkinson's Huntingdon Creutzfeldt-Jacob disease - infectious prions |
| Thermodynamics of protein folding | Stability of the native state is the free energy change of: Denatured > Native or D > N Change in G = G (N) - G (D) A stable native state has a negative change in G |
| How is thermodynamics of protein folding used in disease | Many mutations destabilise proteins by raising the free energy of the native state while leaving the denatured state unchanged, shifting equilibrium away from the native state. |
| How is thermodynamics of protein folding used in treatment | In GPCRs alanine screening mutagenesis more stable receptors have been engineered allowing crystallisation and drug discovery. This involves changing all amino acids to alanine to find a stabilising mutation |
| Free energy of proteins | Change in G = change in H-T(change in S) Typically change in G is between -20 and -60 kJ/mol |
| States of folding | 1. fast collapse and secondary structure formation to form a molton globule state- radius decreases to 10% above native state 2. Appearance of tertiary structure by interactions between secondary structures to increase stability 3. Final formation |
| How to Enzymes assist the formation of disulphide bonds | Protein folding occurs in the ER in the secretory pathway. This involves a disulphide exchange protein and a protein oxidase capable of forming disulphides de novo. The protein disulphide isomerase is oxidised, accepting H from cystine to reduce it |
| What are molecular chaperones | These facilitate folding of proteins by catalytically speeding up the folding process. Three work by unfolding a misfolded protein, facilitating its refolding to the native state, rescuing misfolded proteins. E.g. GroEL-GroES system in E-coli |
| How does the GroEL-GroES system work | Uses ATP to physically pull a misfolded polypeptide chain apart in a low water environment (to reduce hydrophobic effect holding protein together) in order to allow the protein to refold |
| Why do we need cofactors | A range of chemical properties required to sustain life are not available from amino acids (R groups are unreactive) Many cofactor have functions that are hard to achieve using single functional groups Electron transfer uses: NAD, NADH, H+, H2, ATP, ADP |
| What proteins contain alpha domains | Connective tissue e.g collagens RNA and DNA binding proteins e.g. transcription factors Fibrinogen in blood coagulation Membrane proteins e.g. ion channels, receptors and transporters |
| What are coiled- coil alpha helixes | An isolated alpha helix is only marginally stable in solution. In proteins they stabilise through side chain packing e.g. a coiled coil The amino acid sequence in alpha helixes is repetitive over seven residues -a heptad repeat- h bonds occur more often |
| What do coiled coil alpha helixes look like | Two or more alpha helix chains wound around each other e.g. in collagen |
| What is the Knobs in Holes model | The position of side chains on a cylindrical alpha helix is in a plane parallel with the helical axis of alpha helixes in the coiled coil. This side chains on the first helix have knobs which superimpose between side chain position on the second helix |
| What are 4 helix bundles | A common domain in alpha proteins, with arrangement of alpha helixes in the amino acid sequence adjacent in the 3D structure. Some side chains from all helices are buried in the middle of the bundle to form a hydrophobic core. |
| Give 2 examples of 4 helix bundles | Cytochrome b562 - antiparallel helices Human Growth hormone - parallel helices |
| Where are beta structures found | The second largest group of proteins that are functionally the most diverse e.g. enzymes, transport proteins, antibodies, cell surface proteins, virus coat proteins, out membrane proteins These tend to be antiparallel so two sheets can stack |
| What is an up and down beta barrel | This is obtained if each successive strand is added adjacent to the previous strand and the barrel is closed. This is stabilised by hydrogen bonds and beta hairpins E.g. retinol bindng protein has an up and down beta barrel. |
| What are beta propellers | Antiparallel beta strands can fold to form a twisted propeller like structure observed in neuraminidases (e.g. on the surface of influenza) and in cell cell interaction molecules (e.g. plenix-sempaphorin signalling) |
| What is the structure of beta propellers | Each blade contains 4 antiparallel beta strands 6 blades make up the tertiary structure |
| Types of beta barrel protein | These tend to be rigid with polar amino acids on the inside and nonpolar outside, so they form water channels. $ main types are: 8 stranded OmpA, 12-stranded OMPLA, 16-stranded porin and 22-stranded FepA |
| Why use alpha-beta structures | These are the most frequent and versatile domain structure. These consist of a central parallel or mixed beta sheet surrounded by alpha helices. All glycolic enzymes are alpha/beta structures. Binding crevices are formed by loop regions |
| 3 main cases of alpha/beta structures | TIM barrel (triosephosphate isomerase) Rossman fold (lactate dehydrogenase) Leucine-rich motifs (ribonuclease inhibitor) or horseshoe fold |
| Structure of the TIM barrel | This is associated with enzymes with a catalytic domain of alpha/beta/alpha and regulatory domains of alpha helices. The core of a TIM barrel is packed with hydrophobic amino acids along with three layers of side chains |
| How can we create more versatile proteins | By combining domains e.g. signal transduction receptors and ligand gated ion channels Many proteins can form oligomers, either homo or hetero to increase their functional properties e.g. haemoglobin is a homo oligomer to respond to allosteric regulation |
| Membrane protein structures | These play a crucial role in controlling what enters and exits a cell. These can have amphipathic helixes, where all of the hydrophilic helixes are on one side to help anchor a protein to the membrane. |
| Where are different domains seen in membrane proteins | Alpha helix- recognition, receptors Helical bundle- enzymes, transporters, receptors Beta barrel- transporters (channel proteins) |
| Beta barrel porins | In mitochondria, chloroplasts and bacterial e.g. e-coli contain over 100000 porin molecules. These form a water filled channel to allow passive diffusion of nutrients and waste. These allow bacterial to pump out proteins |
| Alpha helical membrane proteins | Fold in several unique folds to form ion channels, transporters, receptors and pumps. Can use ATP to drive ions across the membrane and are responsible for electrical activity in the body as well as playing a role in many diseases |
| Alpha helical channels | These help both passive and active movement of molecules across the membrane e.g drugs, metabolites, ions and signals. Many drugs target these E.g. potassium voltage gated ion channels which open when a positive charge is detected |
| Alpha helical transporters | Transport can be by simple diffusion or via membrane transporters. Three types of transporters: Primary active that use ATP, secondary active that use ion gradients to move molecules and facilitative transported that simple allow molecules to move |
| Glucose transport | This occurs via the GLUT family of passive facilitators which are alpha helical or voa sodium coupled glucose transporters that uses energy of the sodium gradient to move glucose in at the same time. |
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