Molecules of Living Systems (Part-1)

INTRODUCTION

“Life” - integrated result of myriads of interactions between

hundreds and thousands of different molecules of living
systems, collectively called “biomolecules”

To understand life we need to consider the key features of

these molecules, namely:

chemical properties and reactivities

structures and stabilizing forces

different kinds, proportions

mutual interactions

origin during the emergence of the first living cell.

INTRODUCTION

In the present section, we discuss some of the chemical principles

that dictate the properties of biomolecules:

the covalent bonding of carbon with itself and with other

elements

the importance of the three-dimensional structure

(stereochemistry) of carbon compounds as reflected in
biomolecular properties.

the functional groups that occur in common biomolecules

COVALENT BONDING OF SOME IMPORTANT ELEMENTS OF LIVING
SYSTEMS
Hydrogen, oxygen, nitrogen, and carbon are the most abundant
elements in living organisms

These are the lightest

elements having
potential to form one,
two, three, and four
bonds, respectively.

In general, the lighter

elements form the
stronger bonds.
COVALENT BONDING OF SOME IMPORTANT ELEMENTS OF LIVING
SYSTEMS
Sulfur and phosphorus are also common in living systems and
usually participate in two and five covalent bonds, respectively.
BIOMOLECULES ARE ALMOST ALWAYS COMPOUNDS OF CARBON
The chemistry of living organisms is centered on carbon, which
accounts for more than 50% of the dry weight of cells.

Carbon can form

single bonds with
hydrogen atoms, and
both single and
double bonds with
oxygen and nitrogen
atoms.
BIOMOLECULES ARE ALMOST ALWAYS COMPOUNDS OF CARBON
The ability of carbon atoms to share electron pairs with each
other to form very stable carbon–carbon single bonds has
profound biological significance.
Each carbon atom can form
single bonds with one, two,
three, or four other carbon
atoms.
Moreover, two carbon
atoms also can share two (or
three) electron pairs,
forming double (or triple)
bonds.
Triple bonds occur only
rarely in biomolecules,
though.
BIOMOLECULES ARE ALMOST ALWAYS COMPOUNDS OF CARBON

Covalently linked carbon atoms in biomolecules may form linear

chains, branched chains, and cyclic structures.

As a result, carbon atoms can be linked together to form the

backbones of a virtually unlimited variety of biomolecules.
SPATIAL DISPOSITION OF BONDS FORMED BY CARBON
The four single covalent bonds that can be formed by a carbon
atom are arranged in tetrahedral geometry, with an angle of
roughly 109.5° between any two bonds with an average bond
length of 0.154 nm.

There is free rotation around each single bond unless sufficiently

large or charged groups are attached to both carbon atoms that
restrict rotation sterically or electrostatically, as the case may be.
SPATIAL DISPOSITION OF BONDS FORMED BY CARBON
A double bond is shorter (about 0.134 nm) and rigid and permits
negligible rotation (if any) about its axis.

The two doubly bonded carbons and the atoms designated A, B,

X, and Y all lie in the same rigid plane.
MOLECULAR STRUCTURE FROM THREE DIMENSIONAL
PERSPECTIVE

Physico-chemical properties of a biomolecule is greatly

influenced by its stereochemistry — the arrangement of the
molecule’s constituent atoms in three-dimensional space.

Compounds of carbon, including most biomolecules, usually exist

as stereoisomers, different molecules in which the order of
bonding of the atoms and groups is the same, but the spatial
relationship among them is different.

Molecular interactions between biomolecules are always

stereospecific; that is, the molecules can fruitfully interact only
when they have specific relative stereochemistry.
 MOLECULAR STRUCTURE FROM THREE DIMENSIONAL
PERSPECTIVE
Three common ways to illustrate the three dimensional structure of
simple molecules are shown below, using the amino acid alanine as
an example.
Each diagram specifies the structure unambiguously.
(1) Flying-wedge form : a line represents bond
on the plane of the screen, a solid wedge
represents a bond in which the atom at the
wide end projects out of the plane of the
screen, toward the viewer; a dashed wedge
represents a bond extending behind the plane
of the screen.
MOLECULAR STRUCTURE FROM THREE DIMENSIONAL
PERSPECTIVE
Three common ways to illustrate the stereochemical configuration
of simple molecules are shown below, using the amino acid alanine
as an example.
Each diagram specifies configuration unambiguously.

(2) Ball-and-stick model,

where each stick represents a
bond and each ball
represents an atom; a good
way to show relative bond
lengths and the bond angles.
MOLECULAR STRUCTURE FROM THREE DIMENSIONAL
PERSPECTIVE
Three common ways to illustrate the stereochemical configuration
of simple molecules are shown below, using the amino acid alanine
as an example.
Each diagram specifies configuration unambiguously.

(3) Space-filling model, in which

each atom is shown with its relative
van der Waals radius, and hence the
molecular contour signifies the
outer limits of the region from which
atoms of other molecules are
excluded.
MOLECULAR CONFORMATION IS CHANGED BY ROTATION ABOUT
SINGLE BONDS
Molecular conformation refers to the spatial arrangement of
substituents that enjoys the freedom of bond rotation.

Consequently, they may assume different positions in space

without breaking any bonds.

Two possible conformations of ethane arising due to freedom of rotation

around the C—C bond.
MOLECULAR CONFORMATION IS CHANGED BY ROTATION ABOUT
SINGLE BONDS
Thus a large number of different, interconvertible conformations
of simple hydrocarbons like the ethane molecule are possible,
depending on the degree of rotation around the C—C bond .

It is not possible to isolate any of these conformational forms, or

conformers, as the energy differences are small enough to allow
rapid interconversion of the different forms (millions of times per
second).

In biomolecules, however, substituent functional groups, that are

either sufficiently large or electrically charged, may occur,
imparting restriction to the freedom of rotation around the C—C
bond. This limits the number of relatively stable conformations
of such biomolecules.
THE CONFIGURATION OF A MOLECULE IS CHANGED ONLY BY
BREAKING A BOND

Configuration denotes the fixed arrangement of atoms in space in an

organic molecule that depends on the presence of either

(1) double bonds, around which rotation is not allowed, or

(2) chiral centers, around which substituent atoms or groups are

arranged in a specific sequence.

The identifying feature of configurational isomers is that they cannot

be interconverted without temporary breakage of one or more
covalent bonds.
CONFIGURATIONS DICTATED BY THE PRESENCE OF DOUBLE BONDS
Configurations of geometric or cis-trans isomers that differ in the
relative arrangement of their substituent groups with respect to
the “rigid” (rotationally restricted) double bond:

Maleic acid and fumaric acid cannot be interconverted without

breaking covalent bonds, which requires the input of much
energy.
CONFIGURATIONS DICTATED BY THE PRESENCE OF DOUBLE BONDS

Maleic acid and fumaric acid are individually well-defined

compounds that can be separated from the other.

Each have their own unique chemical properties.

A binding site (on an enzyme, for example) that is complementary

to one of these molecules would not be a suitable binding site for
the other, which explains why these compounds have distinct
biological roles despite their similar chemistry.
CONFIGURATIONS DICTATED BY THE PRESENCE OF DOUBLE BONDS
One such striking example is found in the vertebrate retina, where
the initial event in light detection is the absorption of visible light
by 11-cis-retinal. The energy of the absorbed light (about 250
kJ/mol) converts 11-cis-retinal to all-trans-retinal, triggering
electrical changes in the retinal cell that lead to a nerve impulse
CONFIGUARIONS GOVERNED BY ASYMMETRY
A carbon atom with four different substituents is considered to be
asymmetric, and designated as chiral center.

The term chirality (handedness) is derived from Greek chiros,

“hand”.

This concept is used in the context of some stereoisomers that are

related structurally as the right hand is to the left, owing to
different spatial disposition of their substituents.

For a molecule with one chiral center only two stereoisomers are
possible, but for a molecule with two or more (n) chiral carbons,
there can be 2n stereoisomers.
CONFIGUARIONS GOVERNED BY ASYMMETRY

There are four different stereoisomers of 2,3-disubstituted

butanes (n=2 asymmetric carbons, hence 2n=4 stereoisomers).

Each is shown in a box as a flying-wedge formula and a ball-and-

stick model, which has been rotated to allow the reader to view
all the groups.
CONFIGUARIONS GOVERNED BY ASYMMETRY

Some pairs of stereoisomers are mirror images of each

other, and are termed enantiomers.
Enantiomers Enantiomers
(mirror images) (mirror images)
 CONFIGUARIONS GOVERNED BY ASYMMETRY

Pairs of stereoisomers that do not share mirror image relationship

are called diastereomers.

Diastereomers (non-mirror images)

ENANTIOMERS ARE PHYSICALLY DISTINGUISHABLE OWING TO
THEIR DIFFERENTIAL OPTICAL ACTIVITY
Louis Pasteur observed that enantiomers share nearly identical
chemical properties but differ in a particular physical property called
optical activity - interaction with plane-polarized light resulting in
rotation of the plane.

In separate solutions, two enantiomers rotate the plane of plane-

polarized light in equal magnitude but opposite directions
(designated as “+” for clockwise and “-” for anticlockwise rotation).

Hence equimolar solutions of the two enantiomers (racemic

mixtures, a term coined by Pasteur) show no optical rotation.

Molecules without chiral centers do not rotate the plane of plane-

polarized light.
ENANTIOMERS ARE PHYSICALLY DISTINGUISHABLE OWING TO
THEIR DIFFERENTIAL OPTICAL ACTIVITY

+ rotation, clockwise

- rotation, anti clockwise

The enantiomers of the amino acid alanine show opposite

optical activity.
UNAMBIGUOUS DESCRIPTORS OF STEREOCHEMISTRY

Biomolecular interactions are stereospecific: the molecules can

“fit” only when they have certain relative stereochemistry.

Therefore a biomolecule must be named and represented by a

structure so as to make its stereochemistry unambiguous.

Several systems are used for such molecular designation.

UNAMBIGUOUS DESCRIPTORS OF STEREOCHEMISTRY
THE R,S SYSTEM
In the R,S system, each group attached to a chiral center is
assigned with a priority. The relative priorities of some common
substituents are:

The chiral center is viewed with the group of lowest priority (4)
pointing away from the viewer. If the priority of the remaining
three groups (1 to 3) decreases in clockwise order, the
configuration is (R) (Latin rectus, “right”); if in counterclockwise
manner, the configuration is (S) (Latin sinister, “left”).
[Thus each chiral carbon is
designated as either (R) or (S),
which when included in the name of
the molecule provides an
unambiguous description of the
stereochemistry at each chiral
center.]
 UNAMBIGUOUS DESCRIPTORS OF STEREOCHEMISTRY
THE D AND L SYSTEM
The descriptors D and L (an older system for distinguishing
enantiomers), relate the sense of chirality of any molecule to that
of D- and L-glyceraldehyde. D- and L-glyceraldehyde are shown
below in Fischer projection form.
[In a Fischer projection,
the horizontal lines
represent bonds coming
out of the plane of the
paper, while the vertical
lines represent bonds
projecting behind the
plane of the paper.]

The isomer of glyceraldehydes that rotates plane polarized light

to the right (d, dextrorotatory ) was labelled D; while the isomer
that rotates plane polarized light to the left (l, levorotatory ) was
labelled L.
UNAMBIGUOUS DESCRIPTORS OF STEREOCHEMISTRY
D AND L SYSTEM
To name more complex carbohydrates or amino acids, one
draws a similar Fischer projection where the CH2OH or R is on
the bottom and the carbonyl group (aldehyde, ketone, or
carboxylic acid) is on the top. The D descriptor is used when the
OH or NH2 on the penultimate (second from the bottom) carbon
points to the right, as in D-glyceraldehyde, and L is used when
the OH or NH2 points to the left. The following examples illustrate
these points.
CONFIGURATION AND CONFORMATION DEFINE BIOMOLECULAR
STRUCTURES AND HENCE FUNCTIONS

The three-dimensional structure of biomolecules—the combination

of configuration and conformation—is the most crucial for their
biological interactions.

For example, substrate (reactant) binding to the catalytic site of an

enzyme for effective catalysis requires close structural
complementarity of the two molecules.

Similar structural fit is also required in the binding of a hormone

molecule to its receptor on a cell surface, or antigen-antibody
recognition.
 CONFIGURATION AND CONFORMATION DEFINE BIOMOLECULAR
STRUCTURES AND HENCE FUNCTIONS
Complementary fit of a macromolecule and a small molecule:

The image shows a segment of RNA from the regulatory region TAR of
the HIV genome (gray) and argininamide (colored), representing one
residue of a protein that binds to this region. The argininamide fits into
a pocket on the RNA surface and is held in this orientation by several
noncovalent interactions with the RNA.
INTERACTIONS BETWEEN BIOMOLECULES ARE STEREOSPECIFIC

In living systems, chiral molecules are usually present in only one

of their alternative chiral forms.

The amino acids, the building blocks of proteins, occur only as the
L isomers.

Glucose, the monomeric subunit of starch, exists biologically in

only one of its chiral forms, the D isomer.

Chiral compounds in living cells are produced in only one chiral

form because the enzymes that catalyze their synthesis are also
chiral molecules.
INTERACTIONS BETWEEN BIOMOLECULES ARE STEREOSPECIFIC

In contrast, when a compound with a chiral carbon atom is

chemically synthesized in the laboratory, the nonbiological
reactions usually produce all possible chiral forms in an
equimolar mixture and the product obtained does not rotate
plane-polarized light (a racemic mixture).

The individual chiral forms in such a mixture can be separated

only by painstaking physical methods (Pasteur separated
crystals of enantiomeric pairs with forceps).
INTERACTIONS BETWEEN BIOMOLECULES ARE STEREOSPECIFIC

Stereospecificity, the ability to distinguish between

stereoisomers, is exhibited by enzymes and other proteins and is a
pivotally important characteristic feature on which the molecular
logic of living cells has been developed.

For example, the food we eat is largely made of molecules of one

mirror-image form. If we were to eat food that was somehow
made of molecules with the unnatural mirror-image form, we
would likely starve because the enzymes in our bodies are chiral
and preferentially recognize the natural mirror-image form of
their substrates.
INTERACTIONS BETWEEN BIOMOLECULES ARE STEREOSPECIFIC

A diagram
showing how only
one amino acid in
a pair of
enantiomers can
interact in an
optimal way with
a hypothetical
binding site (e.g.,
in an enzyme).
ENANTIOMERS AND THE SENSE OF SMELL
Research suggests that the odor of a particular molecule is
determined more by its shape than by the presence of a particular
functional group.

For example, hexachloroethane (Cl3CCCl3) and cyclooctane have

no obvious structural similarities, but they both have a camphor-
like odor, a fact attributed to their similar spherical shape.

Each molecule binds to spherically shaped olfactory receptors

present on the nerve endings in the nasal passage, resulting in
similar odors.
 ENANTIOMERS AND THE SENSE OF SMELL

Cyclooctane and other molecules similar in shape bind to a

particular olfactory receptor on the nerve cells that lie at the top
of the nasal passage. Binding results in a nerve impulse that
travels to the brain, which interprets impulses from particular
receptors as specific odors.
ENANTIOMERS AND THE SENSE OF SMELL
Some enantiomers interact with chiral smell receptors, and hence
have different odors. There are a few well-characterized examples
of this phenomenon in nature. For example, (S)-carvone is
responsible for the odor of caraway, whereas (R)-carvone is
responsible for the odor of spearmint.
CHIRAL DRUGS
Action of drugs on human has been found to be highly dependent
on the stereochemistry of the asymmetric center of the chiral drug
molecules. For example the enantiomer of the pain killer Darvon
acts as a cough suppressant (Novrad).
VERSATILITY OF BIOMOLECULES OWES LARGELY TO THEIR
FUNCTIONAL GROUPS

Various groups of other atoms, called functional groups, are

added to the carbon skeletons of biomolecules and impart
specific chemical properties to the molecule.

This indicates that the bonding versatility of carbon was possibly

the major factor in the selection of carbon compounds (organic
compounds) as the molecular repertoire of cells during the
origin and evolution of living systems.

No other chemical element has been found to form molecules

of such versatility in terms of sizes and shapes or with such a
variety of functional groups (and hence chemical properties).
 COMMON BIOMOLECULAR FUNCTIONAL GROUPS
Typical examples functional groups found in biomolecules are
shown below.

[All groups are shown in their uncharged (nonionized) form. We use R to represent “any
substituent.” It may be as simple as a hydrogen atom, but typically it is a carbon-containing
moiety. When two or more substituents are shown in a molecule, we designate them R1, R2,
and so forth.]
 COMMON BIOMOLECULAR FUNCTIONAL GROUPS
Typical examples functional groups found in biomolecules are
shown below.

[All groups are shown in their uncharged (nonionized) form. We use R to represent “any
substituent.” It may be as simple as a hydrogen atom, but typically it is a carbon-containing
moiety. When two or more substituents are shown in a molecule, we designate them R1, R2,
and so forth.]
 COMMON BIOMOLECULAR FUNCTIONAL GROUPS
Typical examples functional groups found in biomolecules are
shown below.

[All groups are shown in their uncharged (nonionized) form. We use R to represent “any
substituent.” It may be as simple as a hydrogen atom, but typically it is a carbon-containing
moiety. When two or more substituents are shown in a molecule, we designate them R1, R2,
and so forth.]
BIOMOLECULES MAY CONTAIN MULTIPLE DIFFERENT
FUNCTIONAL GROUPS
Many biomolecules are polyfunctional, containing two or more
different functional groups, each with its own chemical
characteristics and reactivity.

The chemical “personality” of such compounds, is determined by

the chemistry of its functional groups and their stereochemistry.

(an amino acid found in proteins) (a hormone)

BIOMOLECULES MAY CONTAIN MULTIPLE DIFFERENT
FUNCTIONAL GROUPS

(a carrier of acetyl groups in many enzymatic reactions)