Multilevel computational modelling of human diseases

1. Computational and experimental aspects of biomolecular interactions from drug design to nano-biomaterials
Physical Chemistry of biomolecules (4h)
Historical and conceptual introduction to the relationship between experimental and computational techniques for the determination of macromolecular structure, dynamics and interactions.
The nature of intramolecular and intermolecular forces that shape biomacromolecules: physical chemistry of aminoacids, nucleic acids, sugars and lipids and of their interaction with various solvents; structure, dynamics and shape of biomacromolecules; folding models/mechanisms of biomacromolecules; intramolecular interactions of biological and pharmaceutical interest.
Databases of biomacromolecular structures and their visualization/representation.

Experimental physical investigation of biomolecular interactions (7h)
Physical principles of the interaction with matter of radiation and subatomic particles.
Experimental methods for the investigation of the structure and interactions among macromolecules in solution: the physical principles at the basis of different experimental methodologies will be addressed, as well as the main application in the biomedical field, with specific attention to the applications devoted to the investigation of the molecular basis of diseases as well as to drug delivery systems development (eg. protein-protein interaction, macromolecules-cell membrane interaction, extracellular vesicles, nanoparticles for drug and gene delivery). The experimental methods mentioned will be: scattering and diffraction of light, X-ray and neutrons, reflectometry of X-ray and neutrons, isothermal tritation calorimetry, surface plasmon resonance, Fourier transform infrared spectroscopy, circolar dichroism, Langmuir films, atomic force microscopy, nuclear magnetic resonance.

Numerical modelling of biomolecules structures and of their interactions (10h)
General principles of computational modelling of biomolecules: elements of statistical thermodynamics, introduction to molecular mechanics, the concept of force field, solvent models, periodic boundary conditions, geometry optimization/energy minimization.
From experiments to structures and models: the classical Monte Carlo and the simulated annealing algorithms. Examples and hands-on practicals will focus on NMR and SAXS data.
From structures to predictions and data interpretation: the Molecular Dynamics method and molecular docking. Examples and hands-on practicals will focus on protein-drug interactions.

Special topics
Elements of advanced computational techniques for drug discovery and for the characterization of of protein-drug interactions (Potential of Mean Force, Umbrella Sampling, Free Energy Perturbation, Molecular Mechanics Poisson-Boltzmann Surface Area).
New frontiers of biophysical chemistry applied to translational medicine (protein condensates, nano-biomaterials).

2. Creating in silico models of diseases
Introduction: common computational and experimental methods in systems biology.
Protein-Protein Interactions (PPIs), transcriptional control networks and signal transduction networks.
In Silico Models of Cells: advantages, disadvantages, and applications to diseases.
Computational modelling of biological data in the context of diseases: nanopore sequencing, single-cell multi-omics, CRISPR-based systems.