Protein Classification and Structure Prediction Amino acid ...

Ideas on protein folding
• It is believed that hydrophobic collapse is a key
driving force for protein folding
• Hydrophobic core!
• Proteins are, in fact, only marginally stable
• Native state is typically only 5 to 10 kcal/mole more
stable than the unfolded form
• Many proteins help in folding
• Protein disulfide isomerase – catalyzes shuffling of
disulfide bonds
• Chaperones – break up aggregates and (in theory)
unfold misfolded proteins
What determines fold?
• Anfinsen’s experiments in 1957 demonstrated
that proteins can fold spontaneously into their
native conformations under physiological
conditions. This implies that primary structure
does indeed determine folding or 3-D 3 D structure.
• Some exceptions exist
• Chaperone proteins assist folding
• Abnormally folded Prion proteins can catalyze
misfolding of normal prion proteins that then
aggregate
Other factors
• Physical properties of protein that influence
stability & therefore, determine its fold:
• Rigidity of backbone
• Amino acid interaction with water
• Hydropathy index for side chains
• Interactions among amino acids
• Electrostatic interactions
• Hydrogen, disulphide bonds
• Volume constraints
CASP changed the
landscape
• Critical Assessment of Structure Prediction competition.
Even numbered years since 1994
• Solved, but unpublished structures are posted in May,
predictions due in September
• Various categories
• Relation to existing structures, ab initio, , homology, fold, etc.
• Partial vs. Fully automated approaches
• Produces lots of information about what aspects of the
problems are hard, and ends arguments about test sets.
• Results showing steady improvement, and the value of
integrative approaches.
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