3D structure of proteins Flashcards
(15 cards)
what is the folding of a polypeptide determined by?
→the amino acid sequence
→ the molecular structure and properties of its amino acids
→ the molecular environment (solvent and salts)
what is the structure of the peptide bond and what gives the chain movement?
→the peptide bond is a flat planar structure that has a fixed arrangement.
→rotational freedom of the bonds confers movement of the remainder of the chain.
what do polypeptides adopt a structure based on? and what does the energy state depend on?
→Polypeptides adopt a structure based on energy minimization.
→Each molecular structure has a specific energy state.
→The minimization of this energetic state (the free energy of a molecule “G”) determines the most favourable conformation.
→The change in free energy upon folding is called ∆G.
what is the free energy of any conformation affected by?
affected by the molecular environment:
→ aqueous or lipid membrane
→other proteins or molecules, including salts
→ changes in this environment can induce further conformational change (eg. a receptor binding to a ligand)
what are the forces that determine the folding of a protein? and what are their strengths?
→ COVALENT and NON-COVALENT bonds.
→Weak, non-covalent bonds have 1/20th the strength of covalent bonds.
→overall contribution is significant because the number of non-covalent bonds is far larger than covalent bonds.
what are the 4 sub categories of non covalent bonds?
→CHARGED OR ELECTROSTATIC ATTRACTIONS
falls off exponentially as distance increases, is affected by electrostatic environment (aqueous environment)
→ HYDROGEN BONDS
transient non-covalent bonds
→VAN DER WAALS ATTRACTIONS - DIPOLE:
these weak forces occur between two atoms in non-covalent interactions.
→ determined by their fluctuating charge, and are induced by the proximity of the molecules.
→The attraction at a close distance is balanced by the repulsion due to the proximity that is determined by the Van der Waals radius of an atom.
→HYDROPHOBIC INTERACTIONS: hydrophobic interactions minimise disruption of water network
what are the properties of disulfide bonds?
→disulfide bonds form between the side chains of two cysteine residues.
→The bonds form in an oxidative reaction forming very strong covalent bonds.
→The SH groups from each cysteine cross link.
→This usually occurs in distant parts of the amino acid sequence, but occurs adjacently in the three-dimensional structure.
→disulfide bonds can form on the same (intra-chain) or different (inter-chain) polypeptide chains (eg. insulin left).
what are the orientation amino acid side-chains in α helices and β sheets?
→Hydrogen bonding occurs between the carbonyl and amide groups of the polypeptide backbone.
→The variable side chains protrude outwards from both molecules, the helical α helix and the planar β sheet and participate in folding of the secondary structure.
what is an example of tertiary structure?
→seven transmembrane domain of the thyroid stimulating hormone receptor.
what is an example of quaternary structure?
→combining of the four chains of haemoglobin, comprising of 2 α and 2 β chains.
what happens to the protein in protein misfolding?
→the function of the misfolded protein is almost always lost.
→Secondly, misfolded proteins often have a tendency to self-associate and form aggregates (eg. Huntington’s, Alzheimer’s, Parkinson’s disease, etc.)
→other misfolded proteins result in cellular processing that lead to their degradation.
how does protein misfolding happen?
→somatic mutations in the gene sequence leading to the production of a protein unable to adopt the native folding
→ errors in transcription or translation leading to the production of modified proteins unable to properly fold
→failure of the folding machinery
→ mistakes of the post-translational modifications or in trafficking of proteins
→structural modification produced by environmental changes
→induction protein misfolding by seeding and cross-seeding by other proteins
how does protein misfolding happen in Alzheimers?
→In Alzheimer’s disease, the proteolytic cleavage of Amyloid Precursor Protein (APP) happens
→β-Amyloid (Aβ) is a small protein released as a result of proteolysis from a larger transmembrane protein known as APP, it then forms multimers with a specific structure.
→These interfere with the workings of the synapse, in the hippocampus.
→higher order insoluble aggregates form which contain much crossed β-structure.
→This becomes deposited in plaques, damaging the neuronal cells of brain.
how does protein misfolding happen in cystic fibrosis?2
→the most common mutation is a deletion of Phenylalanine at residue 508 of the cystic fibrosis transmembrane conductance regulator (CFTR) .
→leads to the misfolding of the protein whilst it is still in the ER.
→recognized by the cellular machinery that identifies and processes misfolded protein.
→results in ubiquitination, trafficking of the misfolded protein to the proteasome and degradation.
what are infectious proteins and how do they form?
→Prions are misfolded proteins (PrPSC) that interact with other normal proteins (PrPC).
→Through this interaction, they induce misfolding of the normal protein and polymerisation
→Oligomers form fibrils of misfolded protein.
→This process is reliant upon the concept of energy minimisation, ∆G.
→It is a dynamic process brought about by the interaction of molecules, resulting in a more stable, aggregated structure.
