1. Non covalent interactions in living world.ppt

molecular interactions

1. Covalent Interactions
Interaction of atoms leading to the formation of molecules
under certain conditions
A covalent bond is formed when partially occupied orbitals
of interacting atoms overlap and consists of a pair of
electrons shared by these atoms
Formation or breaking of chemical bonds between 2 atoms
by sharing a pair of electrons to fill an orbital on each atom
Equal or nearly equal sharing --> nonpolar group or molecule
Examples: C–C and C–H bonds (not polar)

2. Covalent interactions establish the structural framework of
the protein molecule, the chemical expression of primary
structure
Backbone conformation constrained by steric restrictions on 
and  torsions
Sidechain conformations are also constrained
Favourable sidechain conformations depend on the sidechain
and also on its neighbours.
S-S Bonds between cysteine residues can form within proteins

3. Covalent interactions (bonds) hold the atoms of biopolymers
and small molecules together and covalent bond energies
are in the order of 100 kcal/mole (400 joule/mole)
Covalent bonds don’t break when proteins fold (or unfold),
when RNA folds, when DNA anneals or when membranes
assemble
Those processes (protein folding/unfolding, etc) are
controlled by non-covalent interactions

4. Non covalent interactions – Electrostatic interactions
At small intermolecular distances ’r’ there exist forces of
repulsion, which with increasing distance are replaced by
forces of attraction
First recognized by J. D. van der Waals during analysis of
deviations from the ideal gas law
if you slow the molecules down by cooling the gas, the
attractions are large enough for the molecules to stick
together eventually to form a liquid and then a solid

5. In hydrogen's case the attractions are so weak that the
molecules have to be cooled to 21 K (-252°C) before the
attractions are enough to condense the hydrogen as a
liquid.
Helium's intermolecular attractions are even weaker - the
molecules won't stick together to form a liquid until the
temperature drops to 4 K (-269°C)

6. Noncovalent interactions lead to the formation of a
molecular cluster – association of molecules or molecular
organization into larger structures such as membranes
Also involved in molecular recognition such as substrate –
enzyme docking
L + M  LM
Leads to physical properties such as solubility, boiling point,
melting point etc

7. Noncovalent interactions are considerably weaker (by 1 or
2 orders of magnitude) than covalent interactions
Noncovalent clusters have a characteristic stabilization
energy of a few kilocalories per mole with closest
intersystem distances of about 2 Å
Noncovalent interactions originate from interaction
between permanent multipoles, between a permanent
multipole and an induced multipole, and finally, between
an instantaneous time variable multipole and an induced
multipole

8. Principles that Govern Protein Structure and Stability

9. Protein Stability
(largely through many weak non-covalent interactions)
Proteins are only marginally stable entities under
physiological conditions
A protein structure is the result of a delicate balance among
powerful countervailing forces

11. Forces that stabilize protein structure
Interactions between atoms within the protein chain
Interactions between the protein and the solvent

12. Inter-molecular
Bonding
Intra-molecular
COVALENTHydrogen bond
Van der Waals
Etc.
, , …
Dipole-dipole
Dipole- Induced dipole
Instantaneous dipole-induced dipoleLondon Dispersion
Relative strengths
dispersion forces < dipole-dipole interactions < hydrogen bonds
Ion-dipole
Cation-Pi
Pi-Pi

13. van der Waals forces (Johannes Diderik van der Waals)
van der Waals forces are also known as London forces
They are weak interactions caused by momentary changes in
electron density in a molecule
Includes :
force between two permanent dipoles (Keesom force)
force between a permanent dipole and a
corresponding induced dipole (Debye force)
force between two instantaneously
induced dipoles (London dispersion force)

14. Dipole Interactions
In a molecule with unlike atoms, electrons are not shared
equally
The tendency of any atom to pull electrons away from other
atoms is characterized by a quantity called electronegativity
In a molecule composed of atoms of various
electronegativities, the atoms with lowest electronegativities
hold partial positive charges and the atoms with the greatest
electronegativities hold partial negative charges
A dipole can interact with point charges (Charge-Dipole
Interaction), other dipoles (Dipole-Dipole Interaction), and can
induce charge distribution in surrounding molecules (Dipole-
Induced Dipole Interaction)

15. F
Br
+
F

Br
+
Diplole-Dipole Interaction
In the covalent bonding between two atoms of very
different electronegativity the bond becomes highly polar
(introducing partial charges on the species)
This dipole can interact with other permanent dipoles
This interaction is stronger than dispersion forces

17. Even though CH
4
has no net dipole, at any one instant its
electron density may not be completely symmetrical,
resulting in a temporary dipole. This can induce a temporary
dipole in another molecule. The weak interaction of these
temporary dipoles constituents van der Waals forces
The surface area of a molecule determines the strength of the
van der Waals interactions between molecules. The larger the
surface area, the larger the attractive force between two
molecules, and the stronger the intermolecular forces

18. Dipole-Induced Dipole Interactions
A molecule with a permanent dipole can induce a dipole in a
second molecule that is located nearby in space
The strength of the interaction depends on the dipole
moment of the first molecule and the polarizability of the
second
Dipole-induced dipole interactions are always attractive and
can contribute as much as 0.5 kcal/mole to stabilization
Dipole-induced dipole interactions fall off with 1/r
4

19. Instantaneous dipole-induced dipole –
London Dispersion Forces
Instantaneously generated dipole (due to asymmetry in
electron charge distribution around the nucleus) on one
atom leads to slight polarization of the atom
( quantum induced instantaneous polarization). This
→
induces a dipole on the neighbouring atom (temporarily)
The strength of the dispersion forces will increase with
number of electrons in the molecule

20. Ion-Dipole
Permanent dipole interacts with an ion
This explains for example the solubility of NaCl in water
The figure below shows the interaction of Na
+
and Cl

ions
interacting with the permanent dipoles in a water molecule

21. Chemicals are made soluble in water by (a) dipole-dipole
interactions
The partially charged positive atoms (hydrogen) of water and
alcohol are attracted to oxygen atom dipoles of water and
alcohol. The carbonyl group of an aldehyde, ketone, or acid can
also be solvated by water.

22. The Alpha Helix has a Dipole Moment

23. Ionic Interactions Are Attractions between Oppositely Charged
Ions
In some compounds, the bonded atoms are so different in
electronegativity that the bonding electrons are never shared:
these electrons are always found around the more
electronegative atom
Eg . Sodium chloride (NaCl) – Written as Na
+
Cl
−
ionic bonds (or interactions) – Results from the attraction of a
positively charged ion — a cation — for a negatively charged ion 
— an anion
Uniform in all directions

24. Charge-charge interactions – Coulomb interactions
At close range, Coulomb interactions are as strong as
covalent bonds
Significant at up to 15 Å in proteins
Can be either attractive or repulsive

25. Na
+
, or K
+
, or Ca
2+
 ions play an important biological role
when they pass through narrow, protein-lined pores, or
channels, in membranes – conduction of nerve impulses,
stimulation of muscle contraction
In aqueous solutions, simple ions of biological significance,
such as Na
+
, K
+
, Ca
2+
, Mg
2+
, and CCl
−
, do not exist as free,
isolated entities. Instead, each is surrounded by a stable,
tightly held shell of water molecules. An ionic interaction
occurs between the ion and the oppositely charged end of
the water dipole, as shown below for the K
+
 ion

26. Ions must lose their shell of water molecules in order to
pass through ion channel proteins; channel proteins can
then selectively admit only Na
+
, or K
+
, or Ca
2+
 ions, a
selectivity essential for nerve function

27. Most ionic compounds are quite soluble in water because a
large amount of energy is released when ions tightly bind
water molecules – Energy of hydration
Salts like Na
+
Cl
−
 dissolve in water because the energy of
hydration is greater than the lattice energy that stabilizes
the crystal structure
In contrast, certain salts, such as Ca
3
(PO
4
)
2
, are virtually
insoluble in water; the large charges on the Ca
2+
 and
PO
4
3
−
 ions generate a formidable lattice energy that is
greater than the energy of hydration

28. The highly polar nature of water allows it to break apart (dissolve)
ionic interactions that hold together many types of salt crystals
(NaCl)

29. Electrostatic Interactions in Proteins
Isolated amino acids (in neutral solution) are zwitter ionic -
this means that although the molecule has no overall charge
it carries both a negatively charged group and a positively
charged group:

30. In a normal protein the amino end carries a positive charge (-
NH
3
+
) and the carboxyl end carries a negative charge (-CO
2
-
)
In some cases (e.g., membrane polypeptides) the ends are
chemically modified to avoid these charges (for instance by
acetylation of the amino end group)
Most of the standard amino acids found in proteins have
uncharged side chain groups. However, there are a number of
basic/acidic residues which are positively/negatively charged
at normal pH: Lys, Arg, Asp, Glu, His
Charged side chains in protein can interact favorably with an
opposing charge of another side chain according to Coulomb’s
law

31. The electrostatic force between two point charges is given by:

32. One can crudely estimate the energetics of a charge-charge
interaction in a protein. The energy of an amine (charge +1) and a
carboxylic acid (charge -1) separated by 4 Å in the interior of protein
is given by:
 

33. Salt Bridges
Salts have the ability to shield electrostatic interactions
A positively charged lysine or arginine residue can form a strong
interaction with a negatively charged Asp or Glu group. – Salt bridge
Normally occur on the surface, as opposed to internally
An exception is when an internal salt bridge is involved in the catalytic
mechanism of an enzyme such as in the Asp-His-Ser triad of serine
proteases

35. Hydrogen Bond – A single hydrogen atom can bond simultaneously
with two other atoms
First proposed in 1920 by Latimer and Rodebush and their advisor,
G. N. Lewis
An acceptor atom (A) that bears a basic lone pair of electrons can
interact favorably with a donor atom (D) that bears an acidic
proton
A stable hydrogen bond requires that both A and D are
electronegative atoms, usually oxygen and nitrogen atoms
Hydrogen bonds are essentially electrostatic in nature
A hydrogen bond is not an acid-base reaction

36. A water molecule is tetrahedral in shape with either a
hydrogen atom or a lone pair of electrons at each apex of the
tetrahedron
Oxygen, which is highly electronegative, withdraws electron
density from the hydrogen atoms

37. The hydrogen atom (partially charged) of one water molecule
interacts with a lone pair of electrons in an orbital of the oxygen
atom of another water molecule.
Hydrogen bond between two water molecules

38. X-ray and neutron diffraction of crystalline ice shows each water molecule
engaged in four hydrogen bonds with intramolecular oxygen-oxygen
distances of 2.76Å
Each oxygen atom is located at the center of a tetrahedron formed by four
other oxygen atoms
Each hydrogen atom lies on a line between two oxygen atoms and forms a
covalent bond to one oxygen (bond length: 1.00 Å) and a hydrogen bond to
the other (hydrogen bond length: 1.76 Å)
The hydrogen atoms are not located midway between oxygen atoms

39. In ice, every water molecule acts as a donor in two hydrogen
bonds and an acceptor in two hydrogen bonds
Ammonia, like water is an excellent hydrogen bonding solvent.
Unlike water, ammonia has a greater number of hydrogen
bond donor sites than acceptor sites
Because of this imbalance, liquid ammonia contains fewer
hydrogen bonds than liquid water. Nitrogen is less
electronegative than oxygen, and so the hydrogen bonds of
ammonia are weaker than those of water

40. Hydrogen bonds of biological importance
c) between two peptide chains, the
carbonyl group of one peptide
bonds to an N-H of another;
(d) between complementary base
pairs in DNA.
(a) between an alcohol and water
or between alcohol
molecules;
(b)between a carbonyl group
and water (X = H, R, OH, OR, or
NH
2
);

41. Hydrogen Bonds in Proteins
Hydrogen bonds are of crucial importance to protein structure. The
ability of main chain carbonyl oxygen to form hydrogen bonds with
the main chain amino groups leads to the possibility of forming
different secondary structures
Under aqueous conditions the main chain carbonyl and amino groups
are stabilized by hydrogen bonds to water even in the unfolded
(random coil) state

43. Many side chain groups in proteins can form hydrogen bonds

44. Hydrogen bonds are observed in both states of a protein
In the native state many of the interactions are
intramolecular, for example one part of the protein will form
a hydrogen bond with another part of the protein
In the denatured state, interactions are intermolecular, (i.e.,
between the protein and water molecules, cations, & anions)
A intramolecular hydrogen bond observed in the native state
will be replaced in the denatured state by several hydrogen
bonds between the protein and water molecules
The same is essentially true for charge-charge, dipole-dipole,
dipole-induced, and fluctuations dipole interactions

45. The Hydrophobic Effect
Hydrophobic substances are those which are highly soluble in
non-polar solvents but only slightly soluble in water
This definition excludes substances which are generally
insoluble because of strong intermolecular cohesion
Hydrophobic substances are non-polar and non-hydrogen
bonding

46. Association of nonpolar groups with each other in aqueous
systems

47. The side chains (R groups) of such amino acids
as
 phenylalanine and leucine are nonpolar and hence interact poorly with
polar molecules like water.
For this reason, most of the nonpolar residues in globular proteins are
directed toward the interior of the molecule whereas such polar groups as
aspartic acid and lysine are on the surface exposed to the solvent.
When nonpolar residues are exposed at the surface of two different
molecules, it is energetically more favorable for their two "oily" nonpolar
surfaces to approach each other closely displacing the polar water
molecules from between them
The strength of hydrophobic interactions is not appreciably affected by
changes in pH or in salt concentration

48. Hydrophobic forces play an important role in the overall structure of
proteins
These hydrophobic forces may also cause proteins to aggregate. If a
protein molecule is placed under strain, it may deform slightly. This
protein deformation is called denaturation. If a protein is irreversibly
denatured, it can longer function as it is supposed to, and the protein
has no value as a product. Thus, there is a limit as to how much
strain a protein molecule can undergo. A slightly denatured
(reversibly denatured) protein may expose its hydrophobic regions,
which are normally located in the center of the molecule and are
normally shielded from the protein molecule's surroundings. If other
protein molecules in the solution are also slightly denatured, the
proteins' hydrophobic regions may interact with each other. In
essence, one protein molecule's hydrophobic region may bond with
another protein molecule's hydrophobic region. Each protein
molecule may interact with several other protein molecules, causing
the formation of a protein aggregate