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44 Cards in this Set
- Front
- Back
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What's molecular modelling? |
A series of things: -Construction of general theory -Translate to math-chemistry-physics -Apply theory to model system via conversion math --> computer algorithms -Perform calcs. & analyze results -Compare with experiments if possible |
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What tools are in the toolbox of molecular modelling? |
- Quantum chemistry: small defined system - Molecular mechs/chems: clump molecules, potential functions/processes - Bioinformatics: modelling new protein struct |
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What are cartesian and internal coordinates? |
Cartesian: rel. positions of all atoms in space (xyz) Internal: connectivities, like cartesian but more precise |
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Why could visualizations of molecules be useful? |
It can help us understand processes and functions |
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What's a force field? |
All the interactions within & between molecules form a force field - in essence a list of numbers |
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What are the requirements for a force field to be useful? |
Be simple enough for quick evaluation, but sufficienly detailed to reproduce salient features of system being modelled |
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Give examples of force fields. Can we just choose randomly which one to use? |
General: AMBER, CHARMM, GROMOS, OPLS Specialized: MMFF We base our choice depending on what is being modelled, and we can't mix the use of force fields. |
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What are bonded vs non-bonded terms in a force field? |
Bonded: energy contained in internal df Non-bonded: describes the interactions between molecules |
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What does most force fields contain? |
- Non-bonded interactions - Bondstretching - Anglebending - Torsional rotation |
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What does a force field look like? |
Depends on the atom types and possible interactions. Typed according to typing rules |
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How can we validate/find potential terms (for charges, vd Waals, stretching & bending, torsional parameters)? |
- Electro potential/QM calc for charges - Crystallography for vd Waals parameters - Spectroscopy for stretching & bending parameters -Quantum mechs, NMR spectroscopy for torsional parameters |
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Why could we be interested in surfaces? |
The different types depict particular properties (density, polarity, volumes/cavities, electrostatics), helpful for e.g. ligand designing. Resulting surface depends on force field |
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What different surface types are there? |
Molecular (Connolly) vd Waals solvent accessible surface |
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What's molecular dynamics (MD) simulations? |
Newton's equation for motion, for all particles => accumulated series of snapshots equals a trajectory which can be analyzed |
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What can we extract from molecular dynamics simulations? |
From the trajectory, extract large no. data & visualize this, e.g. membrane process |
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Give examples of visualization software |
- USCF Chimera - VMD - YASARA |
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Give examples of MD software |
- GROMACS - NAMD - CHARMM |
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How can we obtain protein structure? |
Through homology modelling |
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What determines the folding of a protein? |
The spatial arrangement of sec struct elements & interactions of sidechains and backbone |
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What does comparative homology modelling involve? Name at least 4 of 6 |
- Seq alignment - Secondary struct prediction - Fold recognition/threading - Remote homology/modelling - CASP (Crit. assessment of protein struct predictions) - Genes & genomes (bioinfo in evo studies) |
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What's the rationale behind homology modelling? |
The no. unique protein folds is limited, many proteins have the same fold but little seq similarity --> use concept of homology to determine 3D struct, homologs thought to share common ancestor and common fold |
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What's primary, secondary, tertiary & quartenary structures? |
Primary: the aa seq Secondary: local conformation of protein backbone Tertiary: packing of sec struct into globular domain Quartenary: packing of ind domains into multiple domain prot |
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What's a motif and what different motifs are there? |
Small conserved regions associated with functional/struct feature. Sequence motifs: bio related seqs, often sharing common properties Sec struct motifs: usually comprises 2-3 sec structures e.g. alfa-alfa, beta-alfa-beta Tertiary motifs: helicals, beta-sandwich, beta-barrel |
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What's a protein domain (and compared to motifs)? |
A structurally independent globular unit having an extensive interface (i.e. larger than motifs) |
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What's a multidomain protein? |
Several protein domains in close contact but only covalently joined byflexible peptide chains |
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How do active sites often look, what "consequence" does this give? |
Often clefts => active site residues often on different domains |
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What's the basic assumption when homology modelling? |
The backbone of unknown seq is nearly the same as homolog, known template. Place sidechains of unknown into backbone of template. |
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What's most hard to model? |
The loops |
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What's the basic scheme of homology modelling? |
1) Initial search for homologs 2) Repeat full dynamic programming alignment 3) Predict sec struct elements 4) Struct calcs - build model for target 5) Refine model |
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What's the diffs between different homology model methods? |
How to -place side chains - model non-aligned regions (loops) - relax the 3D model. Metals or not? |
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What can a multiple seq alignment display? |
Helices, beta-sheets, buried vs exposed, consensus of diff methods, which residues seems more important, etc. |
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How do we go from primary struct to secondary? |
Look at each aa, which structure it may form with its neighbours => predict the sec structure |
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How can we quality check our sec structure model? |
- Ramachandran plots - Folding reliability - Model absolute quality |
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For what is docking mostly used? |
Protein-ligand interactions useful in drug development, simulations indicate what compounds to experimentally test. Most common is to search inhibitors, since this does not involve much chemistry. |
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How does ligand based virtual screening (LBVS) work? |
Use info of compounds known to bind --> find compunds with similar features |
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How does structure based virtual screening (SBVS) work? |
When target structure is known --> explicit docking (multiple conforms) into active site & assess quality of fit/interactions |
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In SBVS, what docking algorithms can be used? |
Stochastic, flexible, rigid |
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What do we aim for in SBVS/docking? |
Minimal steric repulsion/overlap |
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What's flexible docking? |
Basically the same strategy as SBVS but with MC or MD simulated annealing. Better but takes longer time |
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What is this called and what is it an example of? |
Right-handed α-helix, it's a secondary structure |
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What is this called and what is it an example of? |
Parallell β-sheet, a secondary structure |
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What is this called and what is it an example of? |
Antiparallell β-sheet, a secondary structure |
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What is this an example of? |
A helical motif |
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What stabilizes tertiary structures? |
Bonding interactions between sidechains: Salt bridges, hydrogen bonds, hydrophobic interactions, disulfidbridges etc. |
