Learning outcomes of the course unit
The course is designed to provide the basic computational biophysics and chemistry knowledge for modelling biological systems and biological interactions. Particular emphasis will be given to molecular dynamics approaches and drug design methodologies for the identification of new lead compounds. During the practical sessions some of the theoretical concepts will be applied.
Basic knowledge of physics, chemistry and biochemistry.
Course contents summary
Structure of proteins and relationship between structure and function. The most important interactions in biological systems, the folding process and the hydrophobic effect. Experimental determination of the protein structure: x-ray crystallography and NMR. The Protein Data Bank and the Electron Density Server. Molecular mechanics and force fields. Calculation of the potential energy and the different energetic contributions. The most known force fields, MM2, Amber, CHARMm, OPLS. Atom type and atom name concepts. Examples of molecular graphic programs. Sequence alignment, BLAST and PSIBLAST. Methods for predicting proteins three-dimensional structure. Simple models, stepwise models and global models (MODELLER, SwissModel). Threading methods and ad initio calculations. Protein dynamics and flexibility. Classical Molecular Dynamics approaches. Parametrization, minimization and equilibration. Analysis of protein cavities and clefts. Essential dynamics, eigenvalues and eigenvectors. Accelerated MD variants. The energetics of biological interactions. The different types of water molecules in proteins and the energetic contribution of water. Modeling the protonation state of ionizable residues in protein binding pockets. Ligand-based drug design. Chemical similarity. Molecular descriptors and QSAR models, PCA and PLS. 3D-QSAR. 3D similarity. Comparative Molecular Field Analysis (CoMFA). Structure-based drug design. Combinatorial chemistry. Docking and scoring algorithms. Problems and limitations of common scoring functions. Libraries of compounds and the ZINC website. Ligand-based and virtual-based virtual screening. Consensus scoring.
A.R. Leach. Molecular Modelling: Principles and Applications. Prentice Hall.
T. Lengauer. Bioinformatics – From Genomes to Drugs. WILEY-VCH.
Oral lessons and practical experiments in the lab.
Assessment methods and criteria
Written report about some of the problems investigated during the theoretical and practical sessions. Discussion and questions about the report.