Protein-Ligand Interactions - UP

Protein- Ligand Interactions

Ou t l i n e

In t r o d u ct i o n
Interm olecular bonding forces

Electrostatic or ionic bonds
Hydrogen bonds
Van der Waals interactions
Dipole- dipole and ion- dipole
i n t er act i o n s
Repulsive interactions
The role of water and hydrophobic
i n t er act i o n s

Ou t l i n e

Li g p l o t
Conclusion
VMD

In t r o d u ct i o n

Ligand: a molecule that binds to a specific site
on a protein or/ ....
The molecule which binds to a protein m olecule
(eg, receptor).

A ligand binds through the interaction of m any weak,
noncovalent bonds which form s with the binding site of a
p r o t ei n .
The tight binding of a ligand depends upon a precise fit to
the surface- ex posed am ino acid residues on the protein.

In t r o d u ct i o n

Substrates, drugs, ligands interacts with
m acrom olecular m olecules by a process
called binding.
The specific areas are called binding sites
Binding sites:

Typically a hallow or canyon on macrom olecule
su r f ace
Allowing sm all m olecules to sink into them
Most ligand interact through interactions known
as intermolecular bonds

In t r o d u ct i o n

University of Surrey

In t r o d u ct i o n

Interm olecular interactions not as strong as
covalent bonds found in the target

Can be formed and broken again
There is an equilibrium between ligands bound
and unbound

The tim e a ligand will bind to a target
depends on the strength of these
i n t er act i o n s
Ligands having a larger num ber of
interactions tend to bind stronger

In t r o d u ct i o n

Functional groups of a ligand is important
in form ing interm olecular bonds.

These groups are referred to as binding groups

The carbon skeleton of ligands play an
im portant role in binding

i.e. The targets binding site contains carbon
skeleton groups which interacts with the
ligands carbon skeleton

The specific regions in the target which
interacts is known as binding regions

In t r o d u ct i o n

Adapted from: An
Introduction to Medicinal
Chemistry by Patrick

Intermolecular bonding forces

There are several types of intermolecular
bonding interactions which differs in
their bond strengths
Protein ligand interactions depends:

The struct ure of the ligand
The functional groups present

Intermolecular bonding forces

Electrostatic or ionic bonds

Is the strongest of intermolecular bonds

Takes place between two groups with opposite
charges i.e. Carbox ylate ion and an am m onium
ion

Intermolecular bonding forces

Strength of bond inversely proport ional to the
distance between the t wo groups
Bond strength dependent on environm ent
Stronger in hydrophobic environm ent
The drop- off effect in ionic bonding strength
with separation is less than other interm olecular
i n t er act i o n s
Usually the m ost im portant interaction during
initial binding of ligands

Intermolecular bonding forces

Hydrogen bonds

Takes place between an electron- rich
heteroatom and a electron- deficient
h yd r o g en

Heteroatom : not a carbon or hydrogen

Intermolecular bonding forces

The eletron- rich heteroatom has to have a
lonepair of electrons and is usually an ox ygen
or nitrogen

The electron- deficient hydrogen is linked by a
covalent bond to an electron negative atom
such as nitrogen or ox ygen

The electron negative atom has a greater attraction
for electrons
The electron distribution in the covalent bond is
weighted towards the electron negative charge
giving the hydrogen a slight positive charge.

Interm olecular bonding forces

These functional groups are known as
hydrogen bond donors (HBD), since they
provide a hydrogen for a hydrogen bond

Intermolecular bonding forces

The functional group that provide the
electron- rich atom to receive the
hydrogen bond is known as the
hydrogen bond acceptor (HBA)

Interm olecular bonding forces

Hydrogen bonds has been viewed as a
weak form of electrostatic bonds

Due to the slight positive HBD and negative
HDA
Unlike other intermolecular interactions an
interaction of orbitals is involved

Intermolecular bonding forces

The orbital containing the lone pair of
electrons on heteroatom (Y) interacts
with the orbitals involved in the bond
between X and H

Resulting in a weak form of sigm a bond
which have an im portant directional
co n seq u en ce
The optim um orientation is where the angle
between X- H and Y equals 180°

180° is the strongest bond
Varies between 130°and 180° for strong Hbonds
Can be as low as 90° for weak HBonds

Intermolecular bonding forces

Important to note is the directionality of the
lone pair of the HBA

i.e. The nitrogen of a pyridine ring is sp2
hybridized and points directly away and out of
plane from the m olecule

Intermolecular bonding forces

HBonds have m oderate strengths and varies
between 16 and 60 kJm ol- 1
The HBonds is 10 times weaker than covalent
bonds and is reflected in the bond lengths

Covalent bonds 1- 1.5Å
HBonds 1.5- 2.2Å

The strength of HBonds depends on the
strength of the HBA and HBD
Most com mon HBA in biology nitrogen and
ox ygen

Nitrogen 1 HBond
Ox ygen 2 HBond

Interm olecular bonding forces

Intermolecular bonding forces

Good HBD's contains

Elect ron deficient proton linked to a ox ygen or
n i t r o g en
The m ore electron deficient the proton the better
it will react as a HBD

i.e. A proton attached to a posit ively charged
quaternary nitrogen is a stronger HBond
donor than those attached to a prim ary or
secondary am ine

Intermolecular bonding forces

Van der Waals interactions

Weak interactions

2- 4kJm ol- 1
Involve the interact ions between hydrophobic
r eg i o n s
Many interactions which m ake strong interact ion
o ver al l

The electronic distribution of neutral, non-
polar regions is never totally even or
sym metrical

Transient areas of high and low elect ron densities
These leads to tem porary dipoles
Dipoles on one m olecule can lead to a dipole on

Interm olecular bonding forces

Hydrophobic regions of Transient dipole in Induced dipole on target and
ligand and target ligand van der Waals interactions

Intermolecular bonding forces

Dipole- dipole and ion- dipole
i n t er act i o n s

Many m olecules have perm anent dipoles
Results from different electronegativities of
different atom s and functional groups
Both ligands and active sites (binding sites) have
d i p o l es
It is thought that dipole m om ents of the ligand
interact with t hat of the binding site.
Aligning the ligand so that the dipole m om ents
are parallel and in opposite directions
Stronger than van der Waals but weaker HBond

Intermolecular bonding forces

An high electron density region on one
m olecule can have an attraction on a low
electron density of another molecule

Intermolecular bonding forces

Ion- dipole interactions

Where a charge or ionic group of one
m olecule interacts with the dipole of another
m olecule

Stronger than dipole- dipole interact ion

Intermolecular bonding forces

Repulsive interactions

Repulsive force also important
If molecules com e to close toe each other
their molecular orbitals start to overlap
Also identical charges

Interm olecular bonding forces

The role of water and hydrophobic
i n t er act i o n s

Important interactions is that of water with
m olecules
Macrom olecular targets ex ist is aqueous
environm ent
Water needs to be stripped before binding
Resulting in tighter binding of ligand

Conclusion

There is various different ways in which a
ligand and its target can interact
Im portance of these interactions

Better understanding of protein- ligand
i n t er act i o n s
Better understanding of catalytic m echanism of
act i o n
Guide site- directed m utagenesis
Guide to m odify ligand for better binding

Li g p l o t

Ligplot is a program used to determ ine
m olecular interactions
Ligplot determ ines:

Hydrogen bonds
Polar interactions
Hydrophobic residues