Protein structural dynamics and thermodynamics from advanced simulation techniques

In this work we apply simulation techniques, namely Monte Carlo simulations and a path integral based method called Dominant Reaction Pathways (DRP) approach, in order to study aspects of dynamics and thermodynamics in three different families of peculiar proteins. These proteins are, for reasons such as the presence of an intermediate state in the folding path or topological constraints or large size, different from ideal systems, as may be considered small globular proteins that fold in a two state manner. The first treated topic is represented by the colicin immunity proteins IM9 and IM7, very similar in structure but with an apparently different folding mechanism. Our simulations suggest that the two proteins should fold with a similar folding mechanism via a populated on-pathway intermediate state. Then, two classes of pheromones that live in temperate and arctic water respectively are investigated. The two types of pheromones, despite the high structural similarity, show a different thermodynamic behavior, that could be explained, according to our results, by considering the role played by the location of CYS-CYS bonds along the chain. Finally, the conformational changes occurring in serpin proteins are studied. The serpins are very flexible, with a large size, more than 350 residues, and slow dynamics, from hours to weeks, completely beyond the possibilities of the simulation techniques to date. In this thesis we present the first all-atom simulations, obtained with the DRP approach, of the mechanism related to serpins and a complete characterization of the serpin dynamics is performed. Moreover, important implications for what concerns medical research field, in particular in drug design, are drown from this detailed analysis.