ENERGY COMPONENTS FOR INTERMOLECULAR NON-COVALENT INTERACTIONS

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY

MCOPS

SUBMITTED TO SUBMITTED BY DR.JAYASHREE.B.S SHIKHA TYAGIPROFESSOR 100602017

CONTENTS

1 INTRODUCTION

2 ENERGY COMPONENTS FOR INTERMOLECULAR NONCOVALENT INTERACTIONS

•ELECTROSTATIC ENERGY

• EXCHANGE REPULSION ENERGY

• POLARIZATION ENERGY

•CHARGE TRANSFER ENERGY

• DISPERSION ATTRACTION

• SUMMARY

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

INTRODUCTION

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

Supramolecular chemistry

POTENTIAL ENERGY CURVES

FOR COVALENT AND NONCOVALENT INTERACTIONS BETWEENTWO ATOMS

THE FRACTION OF "BROKEN" BONDS AT EQUILIBRIUM IS

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.

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,

THE THERMODYNAMIC PARAMETERS OF INTEREST FOR THE REACTIONS

THESE ARE RELATED BY THE EQUATION

∆SENTROPY

STANDARD FREE ENERGY (∆G"),

ENTHALPY ∆H

•ELECTROSTATIC ENERGY

•EXCHANGE REPULSION ENERGY

•POLARIZATION ENERGY

•CHARGE TRANSFER ENERGY

•DISPERSION ATTARACTION

ENERGY COMPONENTS

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

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.

Selective Binding of Antiinfluenza Drugs and Their Analogues to ‘Open’ and ‘Closed’ Conformations of H5N1 Neuraminidase

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

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.

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 TOTHE 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

CHARGE TRANSFER ENERGYWhen 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

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.

SUMMARYUNLIKE 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

REFERENCES1 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

THANkU