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Lecture 13

BIOL 200 Lecture Notes - Lecture 13: Structure Formation, Lysozyme, Hydrophile


Department
Biology (Sci)
Course Code
BIOL 200
Professor
Mathieu Roy
Lecture
13

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Folding is a directed search of conformational space allowing the protein to fold on a
biologically feasible time scale. The Levinthal paradox states that if an averaged sized protein
would sample all possible conformations before finding the one with the lowest energy, the
whole process would take billions of years. Proteins typically fold within 0.1 and 1000 seconds.
Therefore, the protein folding process must be directed some way through a specific folding
pathway. The forces that direct this search are likely to be a combination of local and global
influences whose effects are felt at various stages of the reaction.
Advances in experimental and theoretical studies have shown that folding can be viewed in terms
of energy landscapes, where folding kinetics is considered as a progressive organisation of an
ensemble of partially folded structures through which a protein passes on its way to the folded
structure. This has been described in terms of a folding funnel, in which an unfolded protein has
a large number of conformational states available and there are fewer states available to the
folded protein. A funnel implies that for protein folding there is a decrease in energy and loss of
entropy with increasing tertiary structure formation. The local roughness of the funnel reflects
kinetic traps, corresponding to the accumulation of misfolded intermediates. A folding chain
progresses toward lower intra-chain free-energies by increasing its compactness. The chains
conformational options become increasingly narrowed ultimately toward one native structure.
The organisation of large proteins by structural domains represents an advantage for protein
folding, with each domain being able to individually fold, accelerating the folding process and
reducing a potentially large combination of residue interactions. Furthermore, given the observed
random distribution of hydrophobic residues in proteins, domain formation appears to be the
optimal solution for a large protein to bury its hydrophobic residues while keeping the
hydrophilic residues at the surface.
However, the role of inter-domain interactions in protein folding and in energetics of
stabilisation of the native structure, probably differs for each protein. In T4 lysozyme, the
influence of one domain on the other is so strong that the entire molecule is resistant to
proteolytic cleavage. In this case, folding is a sequential process where the C-terminal domain is
required to fold independently in an early step, and the other domain requires the presence of the
folded C-terminal domain for folding and stabilisation.
It has been found that the folding of an isolated domain can take place at the same rate or
sometimes faster than that of the integrated domain, suggesting that unfavourable interactions
with the rest of the protein can occur during folding. Several arguments suggest that the slowest
step in the folding of large proteins is the pairing of the folded domains. This is either because
the domains are not folded entirely correctly or because the small adjustments required for their
interaction are energetically unfavourable, such as the removal of water from the domain
interface.
The presence of multiple domains in proteins gives rise to a great deal of flexibility and mobility,
leading to protein domain dynamics. Domain motions can be inferred by comparing different
structures of a protein (as in Database of Molecular Motions), or they can be directly observed
using spectra measured by neutron spin echo spectroscopy. They can also be suggested by
sampling in extensive molecular dynamics trajectories and principal component
analysis. Domain motions are important for catalysis regulatory activity transport of metabolites
formation of protein assemblies cellular locomotion
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