The course introduces students to various methods and techniques of simulation, analysis and visualization used in modern modeling of biological interactions. In addition to modeling biomacromolecules and their complexes, the methods used in modeling enzymatically catalyzed chemical reactions will be studied. Students will gain a detailed insight into the latest combined computer and experimental research to understand the computational contribution in design, interpretation, and solving specific problems in biochemistry. Students will acquire practical skills and knowledge in the field of computational biochemistry.
Students will learn about different methods and techniques of simulation, analysis and visualization of simulated complexes of biomacromolecules and enzymatically catalyzed chemical reactions. They will master practical knowledge in using available programs to understand the behavior of biomacromolecules (proteins, lipids, carbohydrates, and DNA and RNA). Acquisition of practical knowledge in the field of computational biochemistry will provide students with a new aspect in understanding biochemical and biological systems whose properties are covered by other courses in biochemistry graduate study of chemistry.
In general, the learning outcomes to which this course contributes are:
-explain and apply modern theoretical methods to describe the structure and properties of substances
-connect the structures of matter and chemical reactivity
-describe and explain the mechanisms of chemical reactions, structural, energy and kinetic changes during specific chemical reactions, and biological and physical processes
-use chemical terminology
-select and creatively use existing models to interpret experimental results
-independent use of scientific and professional literature and other relevant sources of information
-independently monitor the development of new knowledge in the field of chemistry and form an expert opinion on their scope and possible applications
-apply the acquired knowledge and skills in their further professional or academic training
-responsibly approach in the implementation and execution of tasks
1. Describe the structural databases used in modeling biomacromolecules and their complexes with small compounds. Design mutated versions of proteins, build complexes of proteins and small compounds (inhibitors, substrates, oligosaccharides, etc.), then complexes of proteins and nucleic acids, transmembrane proteins in the membrane model.
2. Describe approaches in de novo protein modeling (most commonly used approaches/programs/servers)
3. Explain the modeling of protein-protein interactions
4. Apply force fields used in modeling biomacromolecules and their complexes; Apply parameterization and optimization of constructed complexes and modeling of posttranslational finishing.
5. Apply productive simulations of molecular dynamics.
6. Apply modeling of enzymatically catalyzed reactions: QM, QM / MM, EVB. Calculate activation energies
7. Apply trajectory analysis obtained by simulations of biomacromolecular complexes and enzymatically catalyzed reactions
8. Use visualization programs and show different ways of visualizing proteins
Lecture topics:
Concepts in molecular modeling. Structural databases. Construction of biomacromolecular complexes. Computational methods based on the force field. Molecular mechanics. Molecular dynamics. Force fields used in modeling of various biological macromolecules. Parameterization of built systems. Basic concepts in statistical physics and thermodynamics. Basic algorithms used to optimize built complexes. Types of ensembles. Boundary conditions. Modeling of membranes, lipids and membrane proteins and peptides. Modeling of glycoproteins and carbohydrates. Nucleic acid modeling of DNA / RNA in complexes with small compounds and/or proteins. Productive molecular-dynamic (MD) simulations. Coarse-grained MD simulations for monitoring conformational changes in proteins. Calculation of Gibbs ligand binding energy. Modeling of enzymatically catalyzed reactions: quantum-mechanical, quantum-mechanical / molecular-mechanical approach and simulations of EVB (empirical valence bond). Calculation of activation energy. Analysis of trajectories obtained in simulations. Programs used for visualization and different ways of visualizing proteins. Programs for simulating enzymatically catalyzed reactions. Data processing programs.
The seminars will cover problem tasks related to the modeling of biomacromolecular complexes.
The content of the seminar includes the following practical activities in the computer classroom:
1. Construction of a complex, where it will be possible to choose whether to model a protein in a complex with a small ligand, a protein in a complex with a nucleic acid fragment, a protein in a complex with an oligosaccharide, a nucleic acid fragment with an intercalator, a transmembrane protein in a membrane model. The protein may also be post-translationally processed (eg glycosylated) and may contain a non-standard amino acid or cofactor. Amino acid substituted protein variants can be used.
2. Parametrization and construction of topology, the process of obtaining parameters for a previously constructed complex that is necessary to perform computer simulations. The use of a particular type of force field depending on the previously constructed complex. Complex solvation.
3. Optimization of geometry, relaxation and heating of the system to operating temperature and performance of classical molecular-dynamic simulations. Use of periodic boundary conditions (PBC), treatment of electrostatic interactions, algorithm SHAKE. Canonical (NVT) and isothermal-isobaric ensemble (NPT).
4. Analysis of molecular-dynamic trajectories. Analysis of specific interactions realized within the modeled complex. Analysis of average distances and angles. Hydrogen bond analysis. Different ways of visualizing.
5. Calculation of Gibbs binding energy. The MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) method implemented in the AMBER software package will be used to estimate Gibbs binding energy.
6. On one selected example of enzymes, enzyme-catalyzed reactions will be simulated using the EVB method in software package Q. Preparation includes parameterization and topology construction, definition of the reactive region, geometry optimization, relaxation and heating of the system to operating temperature dynamic simulations to obtain initial structures for performing FEP simulations (engl. free energy perturbation). Calculation of activation energy and change of Gibbs reaction energy. Display of the structure of the transition state (transition structure). Application of the LRA decomposition method (linear response approximation) to estimate the contribution of active site amino acids to the catalytic effect.
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