Molecular Modelling Flashcards
What is molecular modelling?
Studying a molecular structure and function through model building and computation
What can we do with molecular modelling?
*study ligand-protein interactions
*look at protein folding
*drug design
*calculate molecular properties
What does molecular modelling involve?
*molecular graphics
*molecular dynamics
*molecular mechanics
*QSAR
*homology modelling
*molecular docking
*quantum mechanics
*free energy calculations
What is molecular mechanics?
*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
What is the equation for force fields?
Energy = Ebonded + Enon-bonded
*Ebonded= Ebond-stretch + Eangle-bend + Erotate-along-bend
*Enon-bonded= Evdw + Eelectrostatic
What is a molecular graphics?
Different graphical visualisation of molecules
*wire frame
*stick
*ball and stick
*space filling
How can proteins be represented on a computer?
*C- alpha, trace like
*ribbon like
*cartoon like
How are positively charged and negatively charged residues shown?
*positive = blue atoms
*negative= red atoms
How are hydrophobic residues shown?
Pink spheres
How is protein structure determined using x ray crystallography?
*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
What is a new method being experimented by scientists for use to determine protein structure?
Cryo-electron microscopy
Used for larger molecules
What is a disadvantage of x ray crystallography?
Protein must be small and in a crystal form
What are examples of non computational methods to determine protein structures?
*x ray crystallography
*cryo- electron microscopy
*NMR
*protein data bank
What is the computational source of protein 3D structures?
*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
How do we know what the most stable confirmation of a protein is?
Generate different conformations and compare their steric energy
Using molecular dynamics
What is molecular dynamics?
*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
What can molecular dynamics be used for?
*protein stability
*conformational changes
*protein folding
*molecular recognition ie proteins , DNA
*drug design- use of multiple conformations to study ligand-protein interactions
Why use computer modelling?
*most models too complicated for purely theoretical reasoning
*numerical experiments need accuracy- computers fast enough
What are the overall sources for 3D structures- computational and not?
*nmr
*X-ray crystallography
*homology modelling
Two facts about changed residues in proteins.
*stabilise N and C terminus
*occur on surface or in active sites
What does X on the molecule stability graph mean?
*local energy minimum
Why is energy minimisation used?
To find stable confirmation for molecule
What is a pharmacophore ?
*area of binding which is common to various ligands which bind to it
How can you find a pharmacophore?
*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
What are the advantages of ligand based drug discovery?
*very fast to screen large chemical databases
*method works well- finds ligands
What are disadvantages of ligand-based drug discovery?
*what if molecule binds to different sites?
*flexible molecules require you identify correct active conformation
What are the methods used for computational drug discovery?
*ligand-based discovery
*structure-based discovery
What are the three things needed to carry out a structure based drug discovery?
- Structure of the protein
- Computer representation-library
3.algorithm that predicts how molecule binds and how strong - MOLECULAR DOCKING
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
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
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
What type of fitting should be used in de novo design?
Loose fitting
What drugs were achieved by structure based design?
COX-2 inhibitors
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
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)
