Modellistica computazionale molecolare di complessi proteici con applicazioni a Sclerosi Multipla, Sindrome Fibromialgica e Funzionamento Muscolare

The main objective of this work is to show that clinical individual information and experimental fndings on biological systems can be effectively integrated by computational modelling at an atomistic scale, to provide elucidation of, support to or proposal of functional mechanisms. The complexity of the leaving systems requires specifc approaches for specifc diseases. In this work, I focused on Multiple Sclerosis and the antigen presentation step in the adaptive immune system response as a possible contribution to disease onset and progression, pinpointing a functional mimicry in the self and nonself peptide recognition operated by the predisposing HLA alleles. The Fibromyalgic Syndrome is also discussed and a potential link between diet-derived PAF-like lipids and the activation of a pain molecular pathway mediated by PAFR receptor is proposed. Finally the interaction of Calcium ions and the CASQ protein – relevant for muscle contractions – is analysed, and a model of the ion binding mechanisms and protein polymerization/de-polymerization is discussed. The investigation instrument adopted is the Molecular Dynamics Modeling, and the developed protocols for the preparation, simulation and analyses of each biological system are provided. The therapeutical perspectives of the fndings here presented are related to the design of i) peptides able to interfere with the antigen presentation mechanism and modulate autoimmune response; ii) an individual risk model for multiple sclerosis patients; iii) molecules able to interfere with the PAFR and modulate pain molecular signalling; iv) biomarkers for diagnosis support and clinical tests for the Fibrormyalgic Syndrome; v) molecules able to interfere with the Calcium and CASQ interaction, able to modulate heart beat; vi) personalised diet modulating the introduction of fat possibly contributing to Fibromyalgy.