1. ENERGY COMPONENTS FOR INTERMOLECULAR NON-COVALENT INTERACTIONS
DEPARTMENT OF PHARMACEUTICAL
CHEMISTRY
MCOPS
SUBMITTED TO SUBMITTED BY
DR.JAYASHREE.B.S SHIKHA TYAGI
PROFESSOR 100602017
2. CONTENTS
1 INTRODUCTION
2 ENERGY COMPONENTS FOR INTERMOLECULAR NONCOVALENT
INTERACTIONS
•ELECTROSTATIC ENERGY
• EXCHANGE REPULSION ENERGY
• POLARIZATION ENERGY
•CHARGE TRANSFER ENERGY
• DISPERSION ATTRACTION
• SUMMARY
3. INTRODUCTION
Supramolecular chemistry
THE FORCES THAT HOLD TOGETHER LARGE AND SMALL
MOLECULES, PARTICULARLY WHERE THE LARGE MOLECULE IS A
PROTEIN OR NUCLEIC ACID AND THE SMALL MOLECULE IS AN
INHIBITOR OR SUBSTRATE
FORCES BETWEEN ATOMS ARE CONVENTIONALLY DIVIDED INTO THE TWO
CATEGORIES OF COVALENT AND NONCOVALENT "BONDS."
DRUG-RECEPTOR INTERACTIONS, ON THE OTHER HAND, ARE GENERALLY
INFLUENCED MOST BY WEAKER, NONCOVALENT "BONDS," WHERE ELECTRON
PAIRS ARE "CONSERVED" IN REACTANTS AND PRODUCTS.
EXAMPLE
4. POTENTIAL ENERGY CURVES
FOR COVALENT AND NONCOVALENT INTERACTIONS BETWEEN
TWO ATOMS
THE FRACTION OF "BROKEN" BONDS AT EQUILIBRIUM IS
5. WEAKNESS OF NONCOVALENT BONDS MAKES THEM VERY USEFUL IN
BIOLOGICAL PROCESSES, BECAUSE A SMALL CHANGE IN THE CHEMICAL
ENVIRONMENT (SUCH AS TEMPERATURE, CONCENTRATIONS, OR IONIC
STRENGTH) CAN FORM OR BREAK SUCH A BOND
BEST KNOWN IMPORTANT EXAMPLES OF NONCOVALENT BONDS
•BETWEEN THE STRANDS OF DNA, WHERE HYDROGEN BONDS HOLD THE
DOUBLE HELIX TOGETHER. BETWEEN ENZYME AND SUBSTRATE.
•"RECEPTOR" PROTEIN AND HORMONE,
•ANTIBODY AND ANTIGEN
•INTERCALATOR AND DNA.
6. ENERGY COMPONENTS FOR INTERMOLECULAR
NONCOVALENT INTERACTIONS
kf = The rate constant for association of the complex
kr = The rate constant for dissociation of the complex
Kas = kf/kr affinity, or association constant
The biological activity of a drug is related to its affinity Kas for the receptor,
7. THE THERMODYNAMIC PARAMETERS OF INTEREST FOR THE
REACTIONS
ENTROPY ∆S
ENTHALPY ∆H
STANDARD FREE ENERGY (∆G"),
THESE ARE RELATED BY THE EQUATION
9. ELECTROSTATIC ENERGY
ENERGY BETWEEN THE TWO CHARGES
ALTHOUGH THE CHARGE DUE TO ELECTRON CLOUD IS SMEARED AROUND
THE MOLECULE BUT FOR PRACTICALLY WE CAN CONSISER IT AS CONDENSED AS
POINT CHARGE
THIS BASED ON THE COULAMB’S LAW DIRECTIONALITY AND THE STRENGTH OF
THE ELECTROSTATIC ENERGY DEPENDS ON THE MULTIPLE MOMENTS
10. OF THE INTERMOLECULAR ENERGY COMPONENTS, THE
ELECTROSTATIC IS THE LONGEST RANGE
ION-ION INTERACTIONS DIE OFF AS 1/R; ION-DIPOLE AS 1/R2; DIPOLE-
DIPOLE AS 1/R3.
11. Selective Binding of Antiinfluenza Drugs and Their Analogues to ‘Open’ and
‘Closed’ Conformations of H5N1 Neuraminidase
12. EXCHANGE REPULSION ENERGY
THE PAULI PRINCIPLE KEEPS ELECTRONS WITH THE SAME SPIN SPATIALLY
APART.
THIS PRINCIPLE APPLIES WHETHER ONE IS DEALING WITH ELECTRONS ON
THE SAME MOLECULE OR ON DIFFERENT MOLECULE'S AND IS THE
PREDOMINANT REPULSIVE FORCE
R IS THE DISTANCE BETWEEN MOLECULES OR NONBONDED ATOMS AND A IS A
CONSTANT THAT DEPENDS ON THE ATOM TYPES.
KEY POINT IS THAT THE REPULSIVE ENERGY RISES VERY QUICKLY ONCE THE
ELECTRONS FROM TWO DIFFERENT ATOMS OVERLAP SIGNIFICANTLY
13. POLARIZATION ENERGY
WHEN TWO MOLECULES APPROACH EACH OTHER, THERE IS CHARGE
REDISTRIBUTION WITHIN EACH MOLECULE, LEADING TO AN ADDITIONAL
ATTRACTION BETWEEN THE MOLECULES.
THE ENERGY ASSOCIATED WITH THIS CHARGE REDISTRIBUTION IS
INVARIABLY ATTRACTIVE AND IS CALLED THE POLARIZATION ENERGY.
FOR EXAMPLE, IF A MOLECULE WITH POLARIZABILITY A IS PLACED IN AN
ELECTRIC FIELD.
14. POLARIZATION IS THE ADDITIVE PROPERTY THAT IS POLARISATION OF A
MOLECULE IS EQUAL TO SUM TOTAL OF THE POLARISABILITY OF THE ATOMS
IT IS ROUGHLY PROPORTIONAL TO THE NUMBER OF VALENCE ELECTRONS
AS WELL AS ON HOW TIGHTLY THESE VALENCE ELECTRONS ARE BOUND TO
THE NUCLEI.
UMEYAMA AND MOROKUMA HAVE CALCULATED THE ION-INDUCED
DIPOLE CONTRIBUTION TO THE PROTON AFFINITIES OF THE SIMPLE ALKYL
AMINES.
NH 3 < CH3NH, < (CH3)2NH < (CH3)3N
THEY ATTRIBUTED THE ORDER OF GASPHASE PROTON AFFINITIES IN THE
ALKYL AMINES TO THE GREATER POLARIZABILITY OF A METHYL GROUP THAN
A HYDROGEN
15. CHARGE TRANSFER ENERGY
When two molecules interact, there is often a small amount of electron flow from
one to the other.
For example, in the equilibrium geometry of the linear water dimer HO-H. .
OH2,
the water molecule that is the proton acceptor has transferred about 0.05e- to the
proton donor water .
The attractive energy associated with this charge transfer is the charge transfer
energy.
Although the charge transfer energy is an important contributor to the
interaction energy of most noncovalent complexes IT does not mean that the
charge transfer energy is the predominant force holding the complex together in its
ground state.
For example, the complex between benzene and I,, earlier thought to be a
prototype "charge transfer“ complex, seems to be held together predominantly By
electrostatic, polarization, and dispersion energies in its ground electronic state
16. DISPERSION ATTRACTION
THERE ARE ATTRACTIVE FORCES EXISTING BETWEEN ALL PAIRS OF
ATOMS, EVEN BETWEEN RARE GAS ATOMS (HE, AR, NE, KR, XE), WHICH
CAUSE THEM TO CONDENSE AT A SUFFICIENTLY LOW TEMPERATURE. IT IS
CALLED THE DISPERSION ATTRACTION.
EVEN THOUGH THE RARE GAS ATOMS HAVE NO PERMANENT DIPOLE
MOMENTS, THEY ARE POLARIZABLE, AND ONE HAS INSTANTANEOUS DIPOLE-
DIPOLE ATTRACTIONS IN WHICH THE PRESENCE OF A LOCALLY ASYMMETRIC
CHARGE DISTRIBUTION ON ONE MOLECULE INDUCES AN ASYMMETRIC
CHARGE DISTRIBUTION ON THE OTHER MOLECULE, E.G., '-HeΔ+ . . .'- HeΔ+.
THE NET ATTRACTION IS CALLED DISPERSION ATTRACTION IT DIES OFF AS
1/R6, WHERE R IS THE ATOM-ATOM SEPARATION.
17. SUMMARY
UNLIKE THE TOTAL INTERACTION ENERGY, WHICH CAN BE MEASURED
EXPERIMENTALLY, THE INDIVIDUAL ENERGY COMPONENTS CANNOT.
RARE GAS-RARE GAS INTERACTIONS (He. . .He AND Xe. . .Xe) HAVE ONLY
DISPERSION ATTRACTION.
THE GREATER POLARIZABILITY OF THE XENON ATOMS, CAUSES THE
GREATER DISPERSION ATTRACTION BETWEEN THEM
A SIMPLE MANIFESTATION OF THIS IS THE MUCH HIGHER BOILING
POINT OF XENON THAN HELIUM, CAUSED BY THE GREATER ATTRACTIVE
FORCES IN XENON LIQUID.
ALTHOUGH THESE ENERGIES ARE INDIVIDUALLY FAIRLY SMALL, THEY CAN
ADD IN A MOLECULAR ENVIRONMENT TO SIGNIFICANT ENERGIES
FOR EXAMPLE THE SINGLE LARGEST ATTRACTIVE FREE ENERGY
CONTRIBUTION TO BINDING IN THE STRONGEST KNOWN SMALL
MOLECULE-MACROMOLECULE INTERACTION (BIOTIN-AVIDIN) IS THE
DISPERSION ATTRACTION
18. REFERENCES
1 BURGER'S “MEDICINAL CHEMISTRY AND DRUG DISCOVERY”, 5th
Edition,vol-1 page no-170-175
2 http://pubs.acs.org/doi/abs/10.1021/jp1030224
3 www.newworldencyclopedia.org/entry/Supramolecular_chemistry
