Molecular docking
Part 2
Experimental Methods
1) X-ray crystallography
2) NMR
3) Electron microscopy
4) Site directed mutagenesis
5) Co-immuno-precipitation
6) Binding assays
Experimentally solve the detailed 3D structures of
biomolecules in their association form
Study the strength of interaction forces, their
energetics, understand how molecular structures fit
together
Investigate mechanisms of action
Docking Classification
• Molecular docking classifies biomolecules into
three categories:
1) Small molecules (ligands)
2) Proteins
3) Nucleic acids
• Types of docking systems are:
1) Ligand - ligand
2)Protein - ligand
3) Protein - protein
4) Nucleic acid - protein
5) Nucleic acid – ligand
6) Nucleic acid – Nucleic acid
Definition of the Pose
A pose is a term widely adopted for
describing the geometry of a particular
complex (also called "binding mode")
It refers to a precise configuration which
is characterized not only by the relative
orientation of the docked molecules but
also their respective conformations
Molecular Complementarity
Structures interact like a hand in a glove,
where both the shape and the physico-
chemical properties of the structures
contribute to the fit.
Shape complementarity is the primary
criterion for evaluating the fit in the
computational docking of two candidate
structures
Chemical and physicochemical
complementarity are also important
The importance of energy
• A complex must have a lower potential
energy than its constituent parts, and this
keeps the parts together
• The goal of computational docking is to
find the 3D configuration of the complex
that minimizes the energy
Molecular Flexibility
1) Rigid body docking
ignores the flexibility of the molecules and treats
them like rigid objects
2) Rigid receptor – flexible ligand docking
only the ligand is treated as flexible, receptor is
rigid
3) Flexible receptor – flexible ligand docking
both protein and ligand are treated as flexible.
Components of Docking Software
1) Molecular representation
2) Searching algorithm
3) Scoring method
Molecular representation
The way to represent structures and
properties
There are three representations
commonly used in docking programs:
1) Atomic representation
2) Surface representation
3) Grid representation
Scoring methods
Assess the quality of docked complexes and
guiding the docking algorithm
The binding process that leads to the formation of
a complex between a ligand and its receptor is
controlled by several factors including:
1) The interaction energies between the two
molecules
2) The desolvation and solvation energies
associated with the interacting molecules
3) The entropic factors that occur upon binding
The final free energy of binding will depend on the
overall balance of these factors
Searching algorithm
An efficient search algorithm that
decides which poses to generate
1) Exhaustive search
2) Monte Carlo
3) Genetic algorithms
4) Simulated annealing
5) Tabu search
Interaction Energies
The interaction forces between two molecules
can be divided into:
1) Electrostatic interactions
2) Hydrogen bond interactions
3) Van der Waals interactions
4) Hydrophobic forces
Desolvation Energies
The binding of a ligand to a protein is influenced
by desolvation and solvation where the interacting
entities become partially desolvated
Leads to the formation of favorable interactions
between the ligand and the protein
Hydrophobic contacts are the driving forces:
hydrophobic moieties associate together to reduce
the interactions with the surrounding water
Another important energy term is electrostatic
interaction between charged atoms and water
molecules
Entropic Effects
• The flexibility of the molecules and the
consequences in terms of entropy can
have a significant impact on the binding
energy of a ligand.
Calculation of the Binding Energies
• The binding energy ΔG binding is the energy
required to separate a complex into
separate parts (protein and ligand).
• It is defined as the difference between
the energy of the associated (bound)
form (Ecomplex) and that of the separated
(unbound) molecules (Eprotein and Eligand).
• A complex has a lower potential energy
than its constituent parts.
• This is what keeps them together
Force-Field Calculations
Molecular mechanics can be used to
estimate the internal energy of the
system, which makes it useful for
calculating ΔG
The total energy of a system is described
as the sum of the independent terms of
the force field
The energies obtained by force field
methods can be used directly to
approximate free energies of binding
