MOLECULAR RECOGNITION AND DOCKING ALGORITHM

Natasja Brooijmans & Irwin Kuntz

Pavithra.K.B

INTRODUCTION
Binding between two molecules such that their orientation maximizes the interaction Earlier use
Protein-ligand complex To find and optimize lead compounds

Docking program- key parts

Search Scoring

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

1. Protein-Protein Docking

2. Protein-Ligand Docking

optimized

Docking uses a search and score method

It involves:

Finding useful ways of representing the molecules and molecular

properties. Exploration of the configuration spaces available for interaction between ligand and receptor. Evaluate and rank configurations using a scoring system, in this case the binding energy

However, since it is difficult to evaluate the binding energy because the binding sites may not be easily accessible, the binding energy is modeled as follows: G bind= Gvdw + Ghbond + Gelect + G conform+ G tor + G sol

Flexibility Algorithms
Ligand Flexibility Algorithm
Incremental Construction

Receptor Flexibility Algorithm

Conformer Libraries Monte carlo methods

Monte carlo Algorithms Evolutionary Algorithms Molecular Dynamics Method

Molecular Dynamics Method

Algorithms
Systematic searches
Incremental construction

Stochastic searches
Montecarlo Evolutionary Algorithm
Genetic Algorithm and LamarckianGA

Deterministic searches
Energy minimization methods Molecular dynamics simulations

Incremental Construction
Anchor and grow method Divide a ligand rigid and flexible. Rotatable bonds Takes lowest n pose next level- Greedy algorithm. DOCK 4.0, FlexX Hammerhead- fragments- database screening.

Monte Carlo Algorithm

Ligand is considered as whole Random changes- translation, rotation & torsion. Each move- structure is minimized First cycle- high temperature (Simulated annealing MC)- Autodock Metropolis selection criterion= Local energy minimization+ surface based solvation energy+entropy calculation Structure accepted or rejected. Prodock

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

At high temperatures, many higher energy solutions will be accepted; at low temps., majority of probabilistic moves rejected

Evolutionary Algorithm
Stochastic method similar to MC methods Finds global energy minimum Fittest individuals carried- next generation Random or biased mutation- genetic diversity & prevent premature convergence Cross over permitted in Genetic Algorithm GOLD Autodock GA and LGA (Lamarckian)

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 1 1 1 0 0

0 0

0 1

0 0

0 0

0 0

0 0

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 1 1 1 0 0 20

0 0

0 0 1

13

0 0

0 1

48 52

0 0

0 0 0

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

1 0

0 1

1 1

0 0

0 0

0 0

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

0 0

1 1

1 1

Replacement
Lower scoring individuals create more offspring, higher scoring ones create fewer or none at all Offspring replace parental generation Cycle of selection, mutation, crossover and replacement repeated
0 0 1 1 0 0
15 1

1 0

1 1

1 1

0 1

22

0 1

Fitness landscapes

MOLECULAR DYNAMICS METHODS

Cannot cross energy barriers Easily trapped local minima uneven potential energy
Temperature of the simulation
Two Approaches

Manipulate potential energy

SCORING FUNCTIONS
Accurate Binding free energy- time consuming MM-PBSA & ES/IS methods First-principles Methods DOCK & Autodock - Coulomb and Van der waals force field EUDOC- force field function- without grid

Semi-empirical methods Aqvist and coworkers- The linear interaction energy (LIE)
Kuntz group developed SDOCK combines the van der Waals force field score and the generalized Born-surface area (GB-SA)

Surface area term-favors VDW

Empirical methods Logical extension of Structure Activity Relationship First empirical scoring function LUDI

Reduction in rotational entropy

The Application

HIV-1 Protease and AHA006

HIV-1 Protease in complex with the cyclic sulfamide inhibitor, AHA006 Source: Protein Data Bank Authors: K. Backbro, T. Unge Exp. Method: X-ray Diffraction (2 res.) Primary Citation: Backbro et al, J Med Chem 40 pp. 898 (1997) Polymer Chains: A, B; Residues: 198; Atoms: 1632

Protein (HIV-1 Protease)

Ligand (AHA006)

(Source: PDB)

HIV-1 Protease dimer

(Rasmol)

Initial X-Ray crystallographic positions of protein and ligand

(SYBYL)

Docking Preparation Ligand

Assign charges Define rotatable bonds Rename aromatic carbons Merge non-polar hydrogens Write .pdbq ligand file

Docking Preparation Protein

Add essential hydrogens Load charges Merge lone-pairs Add solvation parameters Write .pdbqt protein file

Docking Preparation Grid

AutoDock uses gridbased docking Ligand-protein interaction energies are pre-calculated and then used as a look-up Grid maps are constructed based on table during atoms of interest in simulation ligand (here CANOSH)

(AutoDockTools)

Original ligand conf SA conformation #67

(SYBYL)

Original ligand conf SA conformation #67

Close-up of previous

(SYBYL)