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Dock Sem

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27 views26 pages

Dock Sem

Uploaded by

el.hadki.hamza
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PPT, PDF, TXT or read online on Scribd
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Molecular Docking

G. Schaftenaar
Docking Challenge
• Identification of the ligand’s
correct binding geometry in the
binding site (Binding Mode)

• Observation:
– Similar ligands can bind at quite
different orientations in the
active site.
Two main tasks of Docking
Tools

• Sampling of conformational
(Ligand) space

• Scoring protein-ligand complexes


Rigid-body docking algorithms
• Historically the first approaches.
• Protein and ligand fixed.
• Search for the relative orientation
of the two molecules with lowest
energy.
• FLOG (Flexible Ligands Oriented
on Grid): each ligand represented
by up to 25 low energy
conformations.
Introducing flexibility:
Whole molecule docking
• Monte Carlo methods (MC)
• Molecular Dynamics (MD)
• Simulated Annealing (SA)
• Genetic Algorithms (GA)

Available in packages:
AutoDock (MC,GA,SA)
GOLD (GA)
Sybyl (MD)
Monte Carlo
• Start with configuration A (energy E A)
• Make random move to configuration B
(energy EB)
• Accept move when:
EB < EA or if
EB > EA except with probability P:
P exp E A  E B  kT 
Molecular Dynamics
• force-field is used to calculate forces on
each atom of the simulated system
• following Newton mechanics, calculate
accelerations, velocities and new
coordinates from the forces.
(Force = mass times acceleration)
• The atoms are moved slightly with respect
to a given time step
Simulated Annealing

Finding a global minimium


by lowering the temperature
during the Monte Carlo/MD simulation
Genetic Algorithms
• Ligand translation, rotation and
configuration variables constitute the
genes
• Crossovers mixes ligand variables from
parent configurations
• Mutations randomly change variables
• Natural selection of current generation
based on fitness
• Energy scoring function determines
fitness
Introducing flexibility:
Fragment Based Methods
• build small molecules inside
defined binding sites while
maximizing favorable contacts.
• De Novo methods construct new
molecules in the site.
• division into two major groups:
– Incremental construction (FlexX,
Dock)
– Place & join.
Placing Fragments and Rigid
Molecules
• All rigid-body docking methods have in
common that superposition of point sets
is a fundamental sub-problem that has
to be solved efficiently:

– Geometric hashing
– Pose clustering
– Clique detection
Geometric hashing
• originates from computer vision

• Given a picture of a scene and a


set of objects within the picture,
both represented by points in 2d
space, the goal is to recognize
some of the models in the scene
Pose-Clustering

• For each triangle of receptor


compute the transformation to each
ligand matching triangle.
• Cluster transformations.
• Score the results.
Clique-Detection

•Nodes comprise of matches between protein and ligand


•Edges connect distance compatible pairs of nodes
•In a clique all pair of nodes are connected
Scoring Functions
• Shape & Chemical Complementary
Scores
• Empirical Scoring
• Force Field Scoring
• Knowledge-based Scoring
• Consensus Scoring
Shape & Chemical Complementary
Scores
• Divide accessible protein surface
into zones:
– Hydrophobic
– Hydrogen-bond donating
– Hydrogen-bond accepting
• Do the same for the ligand surface
• Find ligand orientation with best
complementarity score
Empirical Scoring

Scoring parameters fit to reproduce


Measured binding affinities

(FlexX, LUDI, Hammerhead)


Empirical scoring

G  G0  Grot  N rot Loss of entropy during binding

 Ghb  f R,   Hydrogen-bonding


neutral. H  bonds

 Gio  f R,   Ionic interactions


ionic  int .
 Garom  f R,   Aromatic interactions
arom.int

 Glipo  f R,   Hydrophobic interactions


lipo.cont.
Force Field Scoring (Dock)

Aij Bij
lig prot
qi q j 
Enonbond     12  6 c 
i j rij rij r ij 
Nonbonding interactions (ligand-protein):

-van der Waals


-electrostatics

Amber force field


Knowledge-based Scoring
Function

Free energies of molecular interactions


derived from structural information on
Protein-ligand complexes contained in PDB

Boltzmann-Like Statistics of Interatomic


Contacts.

 
P p ,  l  Pref exp  F  p ,  l 
Distribution of interatomic distances is converted
into energy functions by inverting Boltzmann’s law.

F P(N,O)
Potential of Mean Force (PMF)

 i  seg
ij
r  
Fij r   kB T ln  fVol _corr r  ij 

  bulk 

 ij
seg
r  Number density of atom pairs of type
ij
at atom pair distance r
 bulk
ij
Number density of atom pairs of type
ij
in reference sphere with radius R
Consensus Scoring
Cscore:

Integrate multiple scoring functions to


produce a consensus score that is
more accurate than any single
function
for predicting binding affinity.
Virtual screening by Docking
• Find weak binders in pool of non-
binders
• Many false positives (96-100%)
• Consensus Scoring reduces rate of
false positives
Concluding remarks

Scoring functions are the Achilles’ heel


of docking programs.

False positives rates can be reduced using several


scoring functions in a consensus-scoring strategy

Although the reliability of docking methods is


not so high, they can provide new suggestions for
protein-ligand interactions that otherwise
may be overlooked

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