MODELING OF MOLECULAR INTERACTIONS: FROM PROTEIN-PROTEIN TO HALOGEN BOND

Part I - Microtubules are polymeric structures formed by the self association of tubulin dimers. They are extremely dinamical 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 between protofilaments, also known lateral as interaction, using free energy calculations. We were able to identify the most important amino acids for tubulin-tubulin binding and to compare this amino acids with experimental results. The main goal of this study is to perform an atomistic description of the interactions. Part II - Halogen bond is an important non-covalent interaction which is receiving a growing attention in the study of protein-ligand complexes. Many drugs are halogenated molecules and it has been recently shown that many halogenated ligand establish halogen bonds with biomolecules. Halogen bond is established between an halogn atom and a nucleophilic group due to the presence of a region of positive electrostatic potential, σ-hole. This nucleophilic group can be an atom with lone pairs, for example N,O or S or it can be a system of $\pi$ electrons of an aromatic ring. This kind of interaction is identified as C-X/$\pi$. We developed and implented a method to properly evaluate the halogen bond interaction during a docking simulation using Autodock software. We also study study the effect of substituents on Ph-X/$\pi$ systems with DFT calculations with two different functional. We identified the best substituent for both rings and compare the results.