Bioinformatics and Molecular Modeling

The teaching unit of Structural Bioinformatics will provide an overview of bioinformatics techniques useful for dealing with the analysis of proteins, the main pharmacological targets and constituents of biotechnological drugs, introducing students to the logic and theoretical bases on which the most used computational approaches are based (3 CFU).
The teaching units of "Molecular modeling: basic methodologies" (2 CFU) and "Computational methodologies in biopharmaceutical development" (3 CFU) aim to provide the student with the knowledge necessary to understand the theoretical foundations and the fields in which computational chemistry applied to drug design can find valid applications both in the academic and industrial fields, so as to learn to critically evaluate the quality of the results and the limits of these methodologies.

Structural bioinformatics
1. Introduction to bioinformatics
2. Genome organization and evolution
3. Databases, archives and information retrieval
4. Substitution matrices, pairwise and multiple alignments, database search and phylogenetic trees
5. Protein structure and architecture
6. Protein structure prediction and validation: comparative modelling, threading and ab initio approaches
7. Introduction to systems biology

Molecular modeling: basic methodologies
Molecular mechanics and dynamics
1. Elements of statistical thermodynamics
2. Introduction to Molecular Mechanics
a. The force fields
b. Solvent models and periodic conditions
c. Geometry optimization

3. Conformational search (CS)
a. Systematic CS methods
b. Stochastic CS methods

4. Molecular Dynamics (MD)
a. The equations of motion and the calculation of a trajectory
b. The microcanonical (NVE), canonical (NVT) and isothermal-isobaric (NPT) ensembles
c. trajectory analysis (energy profiles, RMSD, RMSF, geometrical parameters, hydrogen-bond, cluster analysis, principal component analysis)
d. Applications and limits of MD

5. Enhanced sampling techniques in MD simulations
a. Simulated annealing
b. Umbrella sampling
c. Replica exchange MD
d. Metadynamics
e. Accelerated MD

6. Calculation of free energy in complex systems
a. The potential of mean force (PMF)
b. Alchemical perturbations (Free Energy Perturbation and Thermodynamic Integration)
c. End-point methods (LIE and MM-PBSA)

Computational methodologies in biopharmaceutical development
1. Introduction to Chemoinformatics
a. Computer-Aided Drug Design (CADD)
b. Ligand-based Vs structure-based approaches
c. Scientific models
d. Computers: typology, hardware, Software

2. Molecule representation on computers
a. Molecular graph
b. Connection tables
c. Structure-based line notations

3. Molecular descriptors
a. Definition and classification
b. Fingerprints
c. Physicochemical, Geometrical and electronic descriptors

4. Quantitative Structure-Activity Relationship (QSAR)
a. History and development
b. Traditional regression QSAR models
c. Elements of Machine Learning and Random Forest Algorithm
d. Classification QSAR models

5. Molecular docking simulations
a. Search algorithms
b. Scoring functions

6. Virtual Screening