An Introduction to Molecular Docking

Yudhi Nugraha

Pengantar Bioinformatika. Molecular Docking 1

 Protein-Protein Interaction

Protein-Protein interaction:
Surface contact, shape complementarity
Intermolecular forces:
Van der Waals, hydrogen bonding, electrostatic force
 Hydrogen Bond

Types of Hydrogen Bond:

N-H … O
N-H … N
O-H … N
O-H … O

r
 4Å structure of nAChR

Ligand binding domain (LB)

 core of 10 β-strands, forming a β-sandwich
 an N-terminal α-helix, two short 310 helices

Transmembrane domain (TM)

 4 α-helices in each subunit (M1-
M4)

Intracellular domain (IC)

 α-helical, some residues still
missing

Unwin, Journal of Molecular Biology, March, 2005

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The Binding Site
 Ligands bind in the interface between two
subunits
> the principal (+) side composed of loops A,
B, C and the complementary side (-)
composed of loops D and E
 Ligand is completely buried in the protein

Ligand sitting
behind the C-loop
of the principal side
of the receptor

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Brejc et. al., Nature, May 2001
The Ligands
Very high affinity for both
 Nicotine nAChR and AChBP

ACh derivative, 10-fold less

 Carbamylcholine binding affinity for AChBP
compared to ACh

 HEPES

successful binding under

crystallization conditions

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Nicotine binding

 Hydrophobic interactions with

surrounding residues
 Hydrogen bonding with Ser349,
Trp350
 it is thought that the bridging water
molecules with Leu515 and Met527
contribute significantly to the
binding of NCT

7
Pengantar Bioinformatika. Molecular Docking
  Figure
showing the
hydrophobic
interactions
mostly exist
between
Trp350 and
Nicotine
 Also between
cys395 and
Nicotine

Pengantar Bioinformatika. Molecular Docking 8

 Protein-DNA Interaction

Protein-DNA
interaction:

• DNA recognition
by proteins is
primarily
mediated by
certain classes of
DNA binding
domains and
motifs
 Protein-RNA Interaction

Protein-RNA
interaction:

• RNA recognition
by proteins is
primarily
mediated by
certain classes of
RNA binding
domains and
motifs
 Protein-Ligand Interaction

Ligand Binding:
A small molecule
ligand normally binds
to a cavity of a
protein.

Why?

Effect of Binding:
Activate, inhibit,
being metabolized or
transported by,
the protein
 Protein-Ligand Interaction

Ligand Binding:
A small molecule
ligand normally binds
to a cavity of a
protein.

Why?

Effect of Binding:
Activate, inhibit,
being metabolized or
transported by,
the protein
 Protein-Ligand Interaction

Ligand Binding:
A small molecule
ligand normally binds
to a cavity of a
protein.

Why?

Effect of Binding:
Activate, inhibit,
being metabolized or
transported by,
the protein
 Protein-Drug Interaction

Mechanism of
Drug Action:

A drug interferes with

the function of a
disease protein by
binding to it.

This interference stops

the disease process

Drug Design:

Structure of disease
protein is very useful
 Protein-Drug Interaction

Mechanism of
Drug Action:

A drug interferes with

the function of a
disease protein by
binding to it.

This interference stops

the disease process

Drug Design:

Structure of disease
protein is very useful
Example of Binding Induced Shape Change

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Example 2: Induced Fit of Hexokinase (blue)
Upon Binding of Glucose (red).

Note that the active site is a pocket within the enzyme.

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What is definition of molecular docking?

• In silico (computer-based) approach

• Identification of bound conformation
• Prediction of binding affinity
• Docking vs. (Virtual) Screening

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• Protein / small molecules
– Enzyme / substrates
– Enzyme / drug
• Protein / protein
– Enzyme / inhibitor
– Inhibitor / modulator
– Macromolecular assemblies
• Protein / nucleic acid
– RNA/DNA / polymerase
– Ribosome / peptide
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• Docking two molecules means constructing
the coordinates of the bound state.
• Bound state is called the complex.
• We require coordinates for the independent
molecules as input
• Molecules move towards each other and
bind/‘dock’
• But aim is to predict their docked
configuration (not describe their motion).

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Background: why do protein-
protein docking?
Aside from helping with virtual screening,
• Protein-protein interaction networks are of
widespread interest in systems biology

• Exist proteins with no information, arising from

genome projects
• And known proteins having as yet unknown
interactions

• Structure prediction technology advances

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The Molecular Docking Problem

Given two molecules with 3D conformations in

atomic details:
• Do the molecules bind to each other? If yes:
• How does the molecule-molecule complex looks like?
• How strong is the binding affinity?
Structures of protein-ligand complexes
• X-ray (PDB: 30,179 entries from X-ray
crystallography, NMR and neutron diffraction)
• NMR
Importance of the protein 3D structures
• Resolution < 2.5Å
• Homology modeling problematic

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Basic Principles
The association of molecules is based on interactions
• H-bonds, salt bridges, hydrophobic contacts, electrostatic
• Very strong repulsive (VdW) interactions on short distances.
Association interactions are weak and short ranged.
• Strong binding implies surface complementarity.
Most molecules are flexible.

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Docking Concept

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Representation of a Cavity

HIV-1 Protease

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Generation of Cavity Model

X-ray structure of HIV protease Molecular surface model at active site

Active site filled with spheres. Sphere centers become potential locations for
ligand atoms.

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Ligand-protein docking concept

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Ligand-protein docking concept
Ligand-Protein Docking Concept

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 Checking Chemical Complementarity in
Ligand-Protein Docking
Potential Energy Between Ligand and Protein:

• A ligand with sufficiently low ligand-protein potential energy is considered as

a drug candidate

• Chemical database can be searched to find which chemical molecules can

be docked to a disease protein with sufficiently low ligand-protein energy
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ありがとう ございます

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