Molecular Modelling Flashcards

1
Q

What is molecular modelling?

A

Studying a molecular structure and function through model building and computation

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2
Q

What can we do with molecular modelling?

A

*study ligand-protein interactions
*look at protein folding
*drug design
*calculate molecular properties

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3
Q

What does molecular modelling involve?

A

*molecular graphics
*molecular dynamics
*molecular mechanics
*QSAR
*homology modelling
*molecular docking
*quantum mechanics
*free energy calculations

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4
Q

What is molecular mechanics?

A

*the root of molecular modelling
*molecules rotate, vibrate and translate to assume favoured conformations as a response to inter and intra molecular forces acting upon them
*energies known as FORCE FIELD- derived from experiment and quantum mechanical calculations

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5
Q

What is the equation for force fields?

A

Energy = Ebonded + Enon-bonded

*Ebonded= Ebond-stretch + Eangle-bend + Erotate-along-bend
*Enon-bonded= Evdw + Eelectrostatic

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6
Q

What is a molecular graphics?

A

Different graphical visualisation of molecules
*wire frame
*stick
*ball and stick
*space filling

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7
Q

How can proteins be represented on a computer?

A

*C- alpha, trace like
*ribbon like
*cartoon like

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8
Q

How are positively charged and negatively charged residues shown?

A

*positive = blue atoms
*negative= red atoms

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9
Q

How are hydrophobic residues shown?

A

Pink spheres

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10
Q

How is protein structure determined using x ray crystallography?

A

*X- ray crystallography
*determines atom arrangement within protein crystal
*ray beams strike crystal and diffract into many directions
*angles and intensities of diffracted beams produce 3D image of ELECTRON DENSITY
*from electron density, MEAN POSITION of atoms determined- and chemical bonds

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11
Q

What is a new method being experimented by scientists for use to determine protein structure?

A

Cryo-electron microscopy
Used for larger molecules

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12
Q

What is a disadvantage of x ray crystallography?

A

Protein must be small and in a crystal form

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13
Q

What are examples of non computational methods to determine protein structures?

A

*x ray crystallography
*cryo- electron microscopy
*NMR
*protein data bank

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14
Q

What is the computational source of protein 3D structures?

A

*homology modelling
*constructs atomic resolution model of target protein from AMINO ACID SEQUENCE and experimental 3D structure of related homologous protein- template
*if no similarity to another protein- use Ab initio modelling

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15
Q

How do we know what the most stable confirmation of a protein is?

A

Generate different conformations and compare their steric energy
Using molecular dynamics

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16
Q

What is molecular dynamics?

A

*Computational method that describes equilibrium and dynamics properties of biological systems
*using newtowns law of motion
*info generated at microscopic level- atomic position and velocities
*CONNECTS STRUCTURE AND FUNCTION- additional info than nmr and x ray crystallography provides
*help find most stable confirmation

17
Q

What can molecular dynamics be used for?

A

*protein stability
*conformational changes
*protein folding
*molecular recognition ie proteins , DNA
*drug design- use of multiple conformations to study ligand-protein interactions

18
Q

Why use computer modelling?

A

*most models too complicated for purely theoretical reasoning
*numerical experiments need accuracy- computers fast enough

19
Q

What are the overall sources for 3D structures- computational and not?

A

*nmr
*X-ray crystallography
*homology modelling

20
Q

Two facts about changed residues in proteins.

A

*stabilise N and C terminus
*occur on surface or in active sites

21
Q

What does X on the molecule stability graph mean?

A

*local energy minimum

22
Q

Why is energy minimisation used?

A

To find stable confirmation for molecule

23
Q

What is a pharmacophore ?

A

*area of binding which is common to various ligands which bind to it

24
Q

How can you find a pharmacophore?

A

*download a protein-ligand complex to computer and identify molecular interactions that hold ligand into binding site
*group positions can then be mapped to produce a pharmacophore

25
What are the advantages of ligand based drug discovery?
*very fast to screen large chemical databases *method works well- finds ligands
26
What are disadvantages of ligand-based drug discovery?
*what if molecule binds to different sites? *flexible molecules require you identify correct active conformation
27
What are the methods used for computational drug discovery?
*ligand-based discovery *structure-based discovery
28
What are the three things needed to carry out a structure based drug discovery?
1. Structure of the protein 2. Computer representation-library 3.algorithm that predicts how molecule binds and how strong - MOLECULAR DOCKING
29
What is molecular docking?
Used in structure based drug discovery- study of how two or more molecules fit together Molecules can be moved within binding site to identify favourable confirmation
30
What are the two directions of structure based drug discovery?
*De novo design- constructing new ligands to fit into binding sites *virtual screening of molecular libraries -to find ligands to fit into binding sites
31
What two methods are used in de novo design of drugs?
*link method- fragments placed into active site in favoured way and linked into one molecule *grow method- one single fragment placed into active site and grown into a molecule
32
What type of fitting should be used in de novo design?
Loose fitting
33
What drugs were achieved by structure based design?
COX-2 inhibitors
34
What are advantages of structure based design?
*structures are in 3D- structure can be manipulated to be seen from any angle, binding sit can be enlarged *small molecules can be docked into various regions to determine their fit
35
What are limitations of structure based drug design?
*coordinates of nmr and x ray crystallography required *uncertain of exact position of each atom (2-2.5A)