Autodock

BY ANOP SINGH RANAWAT anop.perl@gmail.com 09530369530

What is docking?
Prediction of the optimal physical configuration and energy between two molecules Categories of docking 1. Protein-Protein Docking: Both molecules are rigid Interaction produces no change in conformation Similar to lock-and key model

2. Protein-Ligand Docking: Ligand is flexible but the receptor protein is rigid Interaction produces conformational changes in ligand

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AUTODOCK
An Automated Docking Software for Predicting Optimal ProteinLigand Interaction. Download from -:
http://autodock.scripps.edu/downloads/autodock-4-2-x-installation-on-windows

AutoDock has applications in: X-ray crystallography; structure-based drug design; lead optimization; virtual screening (HTS); combinatorial library design; protein-protein docking; chemical mechanism studies

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Components of docking software

1. Search algorithm Generates a large number of poses of a molecule in the binding site Monte Carlo methods (MC) Molecular Dynamics (MD) Simulated Annealing (SA) Genetic Algorithms (GA)

Available in packages: AutoDock (MC,GA,SA) GOLD (GA) Sybyl (MD)

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Components of docking software

2. Scoring function Calculates a score or binding affinity for a particular pose Shape & Chemical Complementary Scores Empirical Scoring Force Field Scoring Knowledge-based Scoring Consensus Scoring
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The Algorithms

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Simulated Annealing
Algorithm modeled after the cooling of a solution to form glass, though its better explained by crystal formation Given a long enough cooling time, molecules will relax into their lowest energy state to form the largest crystals Quick cooling - highly disordered system Slow cooling - highly ordered crystal, with each molecule in its lowest energy state Algorithm simulates either linear or proportional slow cooling

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The SA Algorithm
Uses neighborhood operator N(s) to generate a set of solutions according to a fixed distribution New solution compared to preceding solution, and is accepted if its energy is lower than that of previous solution If new solution has higher energy, it is accepted probabilistically according to Boltzmann distribution (see figure above) At high temperatures, many higher energy solutions will be accepted; at low temps., majority of probabilistic moves rejected Boltzmann probability distribution = e exp(delta E/T) where delta E = energy difference between two solutions, T= temperature Boltzmann finds p(of finding a system with energy E at temp T)

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Pseudocode for SA
Compute a random initial state s n=0, x*n = s // initialize best solution to s and first state to 0 Repeat i = 1, 2, // specify number of temperatures to try Repeat j = 1, 2, , mi // no. of steps to perform for each temp. Ti Compute a neighbor s = N(s) // s = new solution from N(s) if (f(s) <= f(s)) then // if energy of s <= energy of s s = s // accept new solution s if (f(s) < f(x*n)) then // if energy of new solution < x*n = s // energy of best solution of n = n + 1 // state n, replace best with new endif else // otherwise replace s with s using s = s with probability e (f(s) - f(s))/Ti // Boltzmann dist. endif EndRepeat EndRepeat

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How Genetic Algorithms Work A Simple Example

Initial population of binary creatures having 6 genes Each gene has two different alleles, either a 0 or a 1 Three operators: crossover, mutation and selection
1 0 1 0 1 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 1 1 0

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Selection
Selection based on a fitness function f(x) This operator chooses those individuals with the lowest values Those with higher values chosen with a very low probability
1 0 1 0 1 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 1 1 0 20 13 48 52

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Crossover
1 0 1 0 1 0 1 0 1 0 1 0 1 0 1 0 0 0 0 0 0 1 0 1 0 1 1 0 0 1 1 0 0 1 1 0 1 0 1 0 0 0 0 0 0 1 1 0

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Mutation
0 1 1 0 0 1 1 0 1 1 1 0 1 0 0 0 0 0 0 1 1 0 0 1 1 0 0 1 1 0 1 1 1 1 1 0 1 0 0 1 0 1 0 1 1 0

0 0

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Replacement
Lower scoring individuals create more offspring, higher scoring ones create fewer or none at all Offspring replace parental generation Elitism function allows best individual from parent generation to persist, if it is a better solution than new individuals created Cycle of selection, mutation, crossover and replacement repeated

0 1 1 0

0 1 1 0

1 1 1 1

1 0 1 0

0 1 0 1

0 1 1 0

15

22

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Pseudocode for GA
Select an initial population set xi0 = {x10 , x20,, xM0} Determine fitness values f(xi0) for each individual Repeat for g = 1, 2, # of generations
Perform selection Perform crossover with probability Perform mutation with probability Determine fitness f(xig) for new individuals xg* = argmini=1,M f(xig) and yg* = f(xg*) Perform replacement Until stopping criterion (# of generations) is reached

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How GA works in AutoDock

Ligands genes are its x, y and z coordinates These form a unit vector, which is given a randomo rotationoangle between 0 and 360 to form a quaternion Additional genes may represent torsion angles between bonds of the ligand

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Mapping
In standard GA, the genotype (x,y,z coordinates plus rotation and any torsion angles) are mapped to the fitness function f(x) The fitness function value corresponds to each individuals phenotype According to the right hand side of the figure, genotypes of parents with high f(x) values are mutated to form genotypes of children with lower f(x) values
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Selection, Crossover & Mutation

Selection chooses ligands with the lowest fitness (energy) values Crossover exchanges x, y, z coordinates, or rotations or torsions between these ligands Example: Two ligands with xyz coordinates Abc and aBc Crossover results in new individuals with coordinates abc and ABc Mutation operator mutates coordinate or other angle values by adding a random real number according to a Cauchy distribution, which is similar to a Gaussian but has thicker tails

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Replacement
Individuals with betterthan-average fitness receive proportionally more offspring no= (fw fi)/(fw - <f>), fw != <f> where no= number of offspring fi = fitness of individual (energy of ligand) fw = fitness of worst individual in last g generations (typically 10) <f> = mean fitness of population
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Lamarckian Genetic Algorithm

According to left hand side of figure, LGA finds lowest fitness function (energy) values first, then maps these values to their respective genotypes Genetic algorithm plus Solis and Wets local search Better performance than either simulated annealing or genetic algorithm alone

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Step
1. Coordinate le preparaEon
2. AutoGrid calculaEon 3. Docking using AutoDock 4. Analysis using AutoDock Tools (ADT)
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 Get detail autodock.scripps.edu/faqs.../autodock4.../Auto Dock4.2_UserGuide.pdf

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