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LOCAL VS NON-LOCAL
INTERACTIONS IN PROTEIN FOLDING AND STABILITY. AN EXPERIMENTALIST
POINT OF VIEW
Luis Serrano, EMBL
Understanding protein folding and stability involves unravelling
the
mechanisms by which natural proteins attain their special
physical
properties, as compared to random heteropolymers. To explain
these
properties, it has been theoretically proposed that there is an
energy gap
between the native and any of the other possible conformations of
a
protein. This gap requires the native set of non-covalent
interactions
between the amino-acidic residues of a protein to be more
stabilising than
those in all other conformations. There are two types of
non-covalent
interactions in proteins: local and non-local, so defined in
terms of the
distance in the sequence between the interacting residues.
Importantly,
they are geometrically different; local interactions participate
on
defining secondary structure while non-local interactions are
involved on
defining the tertiary structure. Both types of interactions can
be either
sequence independent, those between atoms of the backbone (i.e
a-helix main
chain-main chain hydrogen bond), or dependent on the chemical
nature of the
residues involved. The last group is obviously the more relevant
to the
protein folding problem. A very important question refers to the
specific
roles of local and non-local interactions. Classically, local
interactions
have been considered less important for protein stability and for
attaining
a definite three-dimensional structure. However, they were
assigned an
important role on driving the conformational search during
folding in a
variety of phenomenological models of protein folding. This view
was
sustained by the finding that very short protein fragments could
populate
significantly native-like secondary structure in aqueous
solution.
Nevertheless, other models put the emphasis on the hydrophobic
collapse as
the guiding force in the folding process. More recently, another
view of
protein folding has emerged from statistical mechanics theory and
computer
simulations of folding, in which folding is considered as a
global process.
However, in these new approaches to the problem still the
putative role of
local interactions remains unclear. Some simplistic lattice
simulations
find that secondary structure is mainly the product of protein
compaction
and that optimisation of folding speed requires a small
contribution of
local contacts to the stability of the folded state. A similar
conclusion
has been theoretically drawn for proteins with a nucleation-
condensation
mechanism. On the other hand, off-lattice simulations have shown
that
inclusion of main chain-main chain hydrogen bonding is needed to
obtain a
secondary structure content akin to that found in proteins.
Statistical
mechanical models have also been used to investigate the role of
local
helical signals in guiding the folding of helical proteins. In
these
studies, a similar role is found for local and non-local
interactions on
defining the energy gap. In my talk, I will discuss all the
experimental
evidence available regarding the role of local interactions in
folding and
stability. I will start from the random coil state, analyze the
results
obtained in small peptides and finish with the evidence for and
against in
proteins.
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