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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. ## Back to the list of abstracts