(in Polish) Molecular modeling and computational structural biology 2

- Skill extension in the field of molecular modeling;

- Familiarizing students with molecular modeling software: VMD, MOE, NAMD;

- Introducing the basic laws of classical mechanics and quantum mechanics underlying computer simulations.

Classroom

The subject is devoted to the presentation of the research strategy of biomolecular systems using the methods of theoretical physics and various computer simulation techniques. In particular, issues related to computer-aided drug design will be discussed. Basic and advanced methods such as molecular docking, molecular dynamics, quantum-classical molecular dynamics, free energy computation methods and non-equilibrium molecular-dynamics-based methods will be discussed. During the laboratory, students will carry out three projects, covering the most common problems raised in research in the field of computational biophysics.

Block I: Analysis of the stability of the protein-ligand complex:

Students will use the VMD and NAMD programs to visualize protein trajectory and perform basic computer simulation analyses such as:

- study of changes in thermodynamic and energy parameters;

- describe the changes to the initial system (RMSD, RMSF);

- determination of changes in geometric parameters (analysis of bond lengths, angles, torsion angles);

- defining global structural changes in the simulated system.

Block II: Modeling of the protein-ligand system and ligand affinity analysis:

Students will be introduced to the procedure for performing and analyzing molecular docking and molecular dynamics in the MOE software. Participants will be asked to generate a variety of ligand conformations at the active site, select the best conformation of the inhibitor, and check its stability in the receptor. The main aim of the exercise is to present the students with a computer-aided drug design using physical and statistical parameters, such as the analysis of structural clusters, the characterization of the inhibitor binding mode at the active site, the evaluation of the protein-ligand complex stability and the estimation of ligand-receptor affinity.

Block III: Studying the mechanisms of chemical reactions in the active site:

Students will use quantum-classical molecular dynamics to design new-generation antibiotics that use a covalent bonding mechanism to inactivate enzymes. The main aim of the exercise is to present the participants with various quantum effects observed during chemical reactions, such as the formation and break down of covalent bonds, changing the protonation state, or changing the hybridization of an atom.

Block IV: Non-equilibrium molecular dynamics methods.

- Introduction to perturbation methods.

- Preparation of the system for simulation.

- Conducting simulations with the chosen method.

- Analysis of simulation results and comparison with experimental data.

Block V: Computational determination of binding free energy of a ligand to a receptor.

- Introduction to computational methods for determining binding free energy.

- Performing calculations using a selected method.

- Analysis of results in the context of experimental data.

1. Andrew Leach, Molecular Modelling: Principles and Applications

2. daan Frenkel, Berend Smit, Understanding molecular simulation

3. Mike Williamson, How proteins work

4. current literature references provided during lectures.

Developing skills in modeling of biomolecular systems using methods of quantum mechanics, molecular mechanics and molecular dynamics. The lecture and exercises will prepare students to independently model biomolecular systems using selected methods.

Especially:

- Students will learn to work in the BASH shell as well as molecular modeling software;

- Students will be able to prepare biomolecular complexes using molecular modeling methods;

- Students can simulate molecular dynamics as well as quantum-mechanical calculations to simulate chemical and enzymatic reactions;

- Students learn how to interpret the obtained results in the process of computational drug design;

- Students become familiar with the good practice of reporting and publishing results.

Graded credit. Attendance at exercises and active execution of exercises are required. Evaluation based on the average grade of the partial reports of all exercises.