DOCKING

ALGORITHM
Some common searching algorithms include

 Molecular dynamics
 Monte Carlo methods
 Genetic algorithms
 Fragment-based methods
 Point complementary methods
 Distance geometry methods
 Tabu searches
 Systematic searches
Genetic Algorithms

Genetic Algorithms (GAs) are adaptive heuristic search

algorithm based on the evolutionary ideas of natural selection
and genetic. The basic concept of GAs is designed to simulate
processes in natural system necessary for evolution,
specifically those that follow the principles first laid down by
Charles Darwin of survival of the fittest.
Randomness
Population
Mutation
Crossover
 Overview

GAs were introduced as a computational analogy of adaptive systems. They

are modelled loosely on the principles of the evolution via natural selection,
employing a population of individuals that undergo selection in the presence
of variation-inducing operators such as mutation and recombination
(crossover). A fitness function is used to evaluate individuals, and
reproductive success varies with fitness.

 Randomly generate an initial population M(0).

 Compute and save the fitness u(m) for each individual m in the current
population M(t).
 Define selection probabilities p(m) for each individual m in M(t) so that
p(m) is proportional to u(m).
 Generate M(t+1) by probabilistically selecting individuals from M(t) to
produce offspring via genetic operators.
 Repeat step 2 until satisfying solution is obtained.
Distance geometry methods

Many types of structural information can be expressed as

intra- or intermolecular distances. The distance geometry
formalism allows these distances to be assembled and
three-dimensional structures consistent with them to be
calculated.

An example of a program using distance geometry in

docking problem is DockIt.
Point complementary methods

These methods are based on evaluating the shape and/or

chemical complementarities between interacting molecules.
The interacting molecules are usually modeled in an easy
way, for example using spheres or cubes as atoms. The
ligand description is then rotated and translated to obtain
maximum number of matches between ligand and protein
surfaces, minus the number of volume overlaps.

Examples of programs using point complementary

methods are FTDOCK, SANDOCK, FLOG
Tabu searches

These methods are based on stochastic processes, in which new

states are randomly generated from an initial state (referred to as
the current solution). These new solutions are then scored and
ranked in ascending order. The best new solution is then chosen as
the new current solution and the same process is then repeated
again. To avoid loops and ensure diversity of the current solution a
tabu list is used. This list acts as a memory. It contains information
about previous current solutions and a new solution is rejected if it
reminds a previous solution too much.

An example of docking algorithm using tabu search is

PRO_LEADS.
Systematic searches

These methods systematically go through all possible

conformations and represent the brute force solution
to the docking problem. All molecules are usually
assumed to be rigid and interaction energy is
evaluated from a force field model.
Components of algorithm

The algorithm consists of two stages:

1) Searching and Filtering

2) Scoring.

The first stage is a step-by-step search through all the possible

docking configurations. Stringent filtering criteria retain only a
small fraction of the possibilities. The second stage is the
evaluation of each solution retained to estimate its likelihood of
being an accurate model of the complex.
Searching and Filtering

The atomic coordinates of two proteins are loaded in and one of the
molecules is designated as Target and fixed in search space. The
second molecule, designated as Probe is systematically rotated and
translated in order to evaluate the matching between the surfaces of the
two proteins.

The search space consists of all possible orientations and

conformations of the protein paired with the ligand. With present
computing resources, it is impossible to exhaustively explore the
search space—this would involve enumerating all possible distortions
of each molecule and all possible rotational and translational
orientations of the ligand relative to the protein at a given level of
granularity.
A. Grid Generation

The first step consists of generating the Target Grid. This is a

three-dimensional matrix representing the shape of the target
molecule as a collection of cubic volumes, distinguishing surface
and core regions (blue and gray on the figure below).

Core regions are adjusted to model the

conformational flexibility of side chain atoms upon
protein interaction.

To avoid van der Waals clashes and ensuring

correct intermolecular distance after docking, an
Added Radius of 1 Å is summed to the van der
Waals radii of every atom, prior to surface
digitalization.

Each "snapshot" of the pair is referred to as a pose.

B. Searching the binding space

For every orientation of the Probe molecule

a Probe Grid (similar to the Target Grid) is
generated and moved relative to the Target
Grid in discrete steps of 1Å, which
corresponds to the size of the grid cell.

The rotation is performed in discrete Angular

Steps, which is an adjustable parameter of
the algorithm.
C. Surface Contact Score

Surface complementarity of each docked configuration is evaluated by

counting overlaping surface cubes (green) at molecular interface. The
overlap of surface cubes from one molecule with core cubes from the
other (yellow) is allowed but counts 0 to the Contact Score. Docked
configurations presenting core-core overlaps are discarded.
Every relative position of the two grids is a candidate solution.
However, solution will be kept only if the following conditions are
simultaneously verified:

1. There is no overlap of core regions.

2. The Surface Contact Score (number of overlapping surface cubes) is

greater than the Minimum Contact allowed.

3. When the number of solutions kept has reached Maximum Solutions,

the new candidates must have an Surface Contact Score greater than the
least surface overlap within the solutions already kept.

4. The Side Chain Contact Filter (The role of this filter is to reduce the
number of incorrect solutions kept by excluding them according to other
criteria.) is favorable.
 Scoring
The set of candidate docked structures, retained during Searching
and Filtering, is evaluated and ranked according to their likelihood
of being an accurate model of the native complex. The following
scores are computed for each docked configuration:

Surface Contact Score as measured during the Searching and

Filtering stage.

•Electrostatics Interaction Score, based on the Coulomb model:

                      
             
 •Hydrophobics Score, based on an estimate of the solvation
energy variation caused by the formation of the complex:

                                      
      

•Side Chain Contacts Score, as used in the Side Chain Contact Filter.

Global Score
The overall evaluation of docked solutions is given by the Interaction
Global Score. This is the estimated probability (in percentage) that a
docking solution with that Neural Network response is an accurate model
of the complex.