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

Back to the list of abstracts