FREE ENERGIES IN BIOMOLECULAR SIMULATIONS: FROM PROTEIN-PROTEIN INTERACTIONS TO UNFOLDING INHIBITION

Part I - Microtubules are polymeric structures formed by the self association of tubulin dimers. They are extremely dynamical structures, that can undergo phases of growing and shrinking, playing a key role during cells proliferation process. Due to its importance for mitosis, tubulin is the target of many anticancer drugs currently in use or under clinical trial. The success of these molecules, however, is limited by the onset of resistant tumor cells during the treatment, so new resistance-proof compounds need to be developed. We analyze the protein-protein interactions allowing microtubules formation using molecular dynamics and free energy calculations. We were able to identify the most important amino acids for tubulin-tubulin binding and thus to design peptides, corresponding to tubulin subsequences. These peptides, able to interfere with microtubules formations, were proved to exhibit antitumoral activity. Part II - Understanding the molecular mechanisms that allow some organisms to survive in extremely harsh conditions is an important achievement that might disclose a wide range of applications and that is constantly drawing the attention of many research fields. The simple small organic molecules, called osmolytes, responsible for the high adaptability of these living creatures are well known and of common use; nevertheless a full disclosure of the machinery behind their activity is still to be obtained. We developed a computational approach that, taking advantage of advanced simulation techniques, allowed to fully describe the effects of osmo-protectants on a small hairpin peptide and on a full mini-protein. The computational study allowed to highlight interesting new features and to develop a theory on the “osmoprotection driving force”.