professor david liu and brian tse, life sciences 1a page...

Professor David Liu and Brian Tse, Life Sciences 1a page 23

Lectures 2 & 3: An introduction to the molecules of life1. The molecules of life comprise macromolecules and small molecules2. Understanding the molecules of life: chemical structures and bonding

a. Connectivity versus conformationb. The nature of atomsc. Covalent bonding and formal chargesd. Ionic bondinge. Electronegativity and hydrogen bondsf. The bonding continuum and bond polarity

3. Organic molecules and how to draw thema. The molecules of life are organic moleculesb. The geometries of organic moleculesc. Drawing organic moleculesd. Understanding “arrow-pushing” notation

4. Stereochemistry and the molecules of lifea. Stereoisomers and enantiomersb. Drawing stereoisomersc. The tragedy of thalidomided. Geometric isomerse. The role of geometric isomers in vision

5. The molecular components of HIV


O

OHHO

HO OH

Ribose

C5O5H10

=C C

C

O

C

CO

H

O H

O

H H

H

O

H

H

H

H H

C

CCC

CO

O

H

H

OH O

H

O

H

H

H

H

H H

O

CO C

CCCH

O H

H

H O

H

OH

H

H

H

H

CCC

O

CC

O O

H

H H

H

HH

O H H O

H H

The Richness of Organic Structures

One bondingscheme out of> 200 isomersof C5O5H10

Three other examples of isomers of C5O5H10:

• The number, geometries, and stability of bonds made to carbon atoms impartenormous structural diversity into organic molecules

2. Organic molecules and how to draw them

The molecules of life are organic molecules

In general, the molecules of life contain a carbon backbone. Molecules containing carbonare aptly named organic molecules, and their study is the subject— frequently feared byundergraduates— called organic chemistry. Carbon’s ability to form four covalent bondsenables carbon skeletons to adopt an enormous diversity of three-dimensional shapes, sizes,and flexibilities. Consider ribose, the simple sugar that is found in the backbone of RNA.Even though ribose contains only five carbon atoms, five oxygen atoms, and ten hydrogenatoms, it is only one of more than 200 different ways to connect these atoms in a way thatsatisfies our bonding principles! The different structures that can be assembled from thesame chemical formula (in the case of ribose, C5O5H10) are called isomers.


Geometries of Organic Molecules

Methane

Ethylene

Acetylene

Tetrahedral

Trigonal (planar)

Linear

• A carbon atom adopts a geometry determined by its number of bonding partners(4 = tetrahedral, 3= trigonal, 2 = linear), as dictated by e–/e– repulsion

The geometries of organic molecules

Within organic molecules, each carbon atom and its bonding electrons generally assumeone of three types of geometries: tetrahedral, trigonal, or linear. These geometries can all bepredicted by appreciating that the negatively charged electrons within covalent bonds repeleach other, and therefore distribute themselves around their shared carbon atom to maximizetheir mutual separation. A carbon atom that makes four single covalent bonds to four otheratoms such as the carbon in methane (CH4) lies in the center of a tetrahedron, a four-sidedsolid with each face consisting of an equilateral triangle. This tetrahedral geometry maximizesthe average distance between electrons in the four bonds. In a perfectly symmetrictetrahedron, the angle between any two bonds made to the same carbon atom is 109 degrees.

Likewise, carbon atoms that make one double bond and two single bonds to a total of threeother atoms adopt a trigonal geometry in which the angle between any two bonds is roughly120°, maximally spreading the arrangement of the single and double bonds. As a result,carbon atoms that make bonds to three other atoms occupy the same plane as those otheratoms. For example, both of the carbon atoms in ethylene (H2C=CH2) adopt trigonalgeometries. You may notice that not only do the three bonding partners of each carbon atomlie in the same plane, but that all six atoms in ethylene are coplanar. Ethylene demonstratesan important additional feature of trigonal carbon atoms: when two trigonal carbon atoms areconnected by a double bond, all six of the atoms connected to both carbons lie in the sameplane. As we described earlier, this required six-atom coplanarity arises from the shape of theelectron clouds that form a double bond. In order for the double bond to form, the anglebetween the two trigonal planes must be close to zero. We will return to the biologicalimplications of this requirement shortly.


Non-Carbon Atoms Adopt Analogous Bonding Geometries

Linear Trigonalplanar

N

C

H

O

Hydrogen Cyanide Acetone

CCH3H3C

• The geometries of non-carbon atoms can be deduced by treating non-bondedelectron pairs as “bonds” that are subject to e–/e– repulsion

Finally, carbon atoms that make one triple bond and a single bond adopt a linear geometry.For example, in acetylene the angle between the two H-C bonds is 180 degrees, maximizingthe separation of the electrons in each bond.

The tetrahedral, trigonal, and linear geometries of carbon also apply to other types ofatoms. Nitrogen and oxygen atoms within molecules assume geometries similar to those ofcarbon if you consider their non-bonded electron pairs to be single covalent bonds. Forexample, the triply bonded nitrogen atom of HCN adopts a linear geometry, while the doublybonded oxygen atom of H3C-CO-CH3 (acetone) adopts a trigonal geometry.


Ribose Depicted Six Ways

C C

C

O

C

CO O

O

H

H

H

O

H

H

H

H

H

H

H

CH CH

CH

O

CH

CH2HO OH

HO OH

OHO OH

HO OH

Computer-created models:

Representations that can be drawn by hand:

• What do these lines mean?

Standard drawing

Drawing organic molecules

Scientists depict organic molecules in several different ways. The widespread availability ofpowerful computers makes accurate, three-dimensional models of organic molecules veryaccessible to research scientists and students alike. You will have the opportunity to createand explore models of organic structures on computers in an upcoming LS1a laboratory unit.Among the three computer-generated models of ribose shown above, the first is the simplestand conveys the basic bonded structure of ribose with the most clarity. The second computer-generated model is similar to the first but shows an approximate boundary of electron densityaround each atom. The third model depicts each atom’s electron density as a colored solid.This last model is known as a space-filling model and although it provides an excellent sense ofthe volume occupied by a molecule’s electrons, its opacity can hide important structuralfeatures of a molecule.

In many cases, a computer-generated model is not convenient or necessary. Without theassistance of a computer, ribose can be drawn by hand in several different ways, also shownabove. While the first drawing of ribose is the most complete because every bond and atom isdrawn explicitly, it is rarely used because its clutter obscures the essential features of riboseand it is too laborious to draw. The second drawing is less cluttered and still names each atombut requires that you imagine the bonds between atoms within common groups such as–CH2–.


Standard Drawing Convention forOrganic Molecules

• Lines are covalent bonds• Intersections and termini of lines represent carbon atoms• Each carbon atom is bonded to enough implied hydrogen atoms to

satisfy the octet rule (four bonds total to each neutral carbon atom)• All non-C, non-H atoms must be shown explicitly (P, O, N, Cl, etc.)

HO

OO H

O

NH

CCCCC

C

OC

CCCCC

C

OC

H

H

H

H

H

H H

H

HHHHH

H

C

CCC

CC

NH

C

C

C

C

CC

H

H

H

H

H

H

HH

The third drawing is the easiest to create, the least cluttered, and the best at conveying thebasic shape of an organic molecule (indeed, it most closely resembles the first two computer-generated models of ribose). It is also the way in which organic chemists most frequently depictmolecular structures. To fully deduce the structure of molecules drawn using this thirdconvention requires understanding that (i) lines represent covalent bonds; (ii) carbon atoms lieat the intersection and termini of all lines, and (iii) all carbon atoms are bonded to enoughimplied hydrogen atoms to complete their four-bond requirement. Therefore, the end of a linesignifies a –CH3 group, two lines meeting at an common point signifies a –CH2– group, and threelines meeting at a common point signifies a carbon connected to one hydrogen and three otheratoms. All atoms other than C or H must be labeled with their periodic table symbols. Thisdrawing convention can also be used to depict carbon atoms involved in double bonds and triplebonds. Make sure you can interpret and draw standard organic structures such as the examplesshown here, as this skill will prove useful throughout your studies in the molecular sciences.


Common Groups Found in OrganicMolecules

methyl hydroxyl

amino

carboxylic acid

carbonyl

phosphate

amide carboxylate

ammonium

CH3 Me OH

NH2 NH3

O

OH

O

O

O

NH

OPO

O

O

O

Organic chemistry is full of nomenclature, or naming systems for molecules. Thenomenclature needed to unambiguously name the rich diversity of organic molecules is socomplex that it is easy to spend much more effort learning nomenclature than is reallynecessary to appreciate and understand organic molecules. Those of you who will takeorganic chemistry courses in the future will become acquainted with nomenclature; for now, avery small, but useful, subset of names for groups of atoms commonly found within organicmolecules is shown above. We will refer to these simple groups during the rest of this courseand therefore you should become familiar with their names.


HN

N

N

N

O

O

S O

ON

N

Representations of 3-D Structures On Paper

HN

CNC

CC

C

N

N

CH3O

CC

HC

HCCCH

OH2C

H2C

SO

ON

CH2CH2

N

H2C

H2C

H3C

CH3

CH2

CH3

Sildenafil (Viagra)

• Multiple perspectives arerequired to fullyappreciate the structuresof three-dimensionalmolecules in two-dimensional depictions(stay tuned for lab)

Even with properly drawn structures, it can be challenging to accurately envision three-dimensional structures using two-dimensional representations. For example, in the 2-Drepresentation of Viagra’s structure (above), it is not apparent if the four rings of atoms in thestructure are all coplanar, or if they exist in different planes to form a more complex shape.Only when the structure is viewed from multiple perspectives is the non-planar, complex shapeof Viagra apparent. In the laboratory for this course, you will have the opportunity to explorethree-dimensional models of complex small molecules and macromolecules using computers.You are also encouraged to build plastic models of molecules using model sets to increase yourfamiliarity with organic structures.


Understanding “Arrow-Pushing” Notation• Reaction mechanism: a description of the individual steps by which bonds

are broken and made during a reaction• “Arrow pushing” is a formalism for drawing reaction mechanisms

Simple Rules to Understand Arrow Pushing1) One arrow represents the movement of one PAIR of valence electrons2) The arrow begins where the electrons start (electron-rich atoms or bonds),

and ends where they are going (electron-poor atoms or bonds)

3) An arrow that starts at an atom represents moving a lone pair4) An arrow that starts at the center of a bond represents breaking that bond

5) An arrow that ends at an atom represents forming a new covalent bond ora new lone pair

6) An arrow that ends at a bond represents adding a second (or third) bond

The molecules of life are not inert. Most life processes require the chemicaltransformation of organic starting molecules into new products. The simple knowledge of thestarting materials and products of a chemical reaction is often insufficient to achieve a deepunderstanding of the process. Instead, scientists strive to elucidate the mechanism of areaction, which refers to the individual steps by which bonds are broken and made during atransformation. Knowledge of a reaction’s mechanism is crucial to understanding how aprocess works and how scientists can intervene in the process to facilitate or shut down a givenreaction. As we will see later in the course, for reactions that take place within an HIV-infectedcell, knowledge of reaction mechanism enables scientists to develop specific drugs to interferewith reactions required for HIV replication.

Scientists normally depict reaction mechanisms using a notation called “arrow pushing”(also known as “curved arrow formalism”). Although you will learn how to write your ownarrow-pushing mechanisms when you take organic chemistry, it is useful for this course for youto learn how to interpret a given arrow-pushing mechanism.

There are really only two essential rules underlying arrow pushing. First, one arrowrepresents the movement of one pair of valence electrons. Second, each arrow begins wherethe electrons start, and ends where the electrons are going during a given mechanistic step.The electrons that are most likely to move in a mechanistic step are those associated withelectron-rich atoms or bonds. As you may have guessed, typically these electrons end upassociated with electron-poor atoms or bonds.


O

CH3C N

O

CH3

H

HOH

H

Arrow-Pushing Examples

Deprotonation of a carboxylic acid by an amine

Hydrolysis of an amide

Note: lone pair electrons not involved in a mechanistic step are oftennot drawn but are shown here for clarity.

O

CH3C N

CH3

O H

OH

HH

OC

O

H3CH

HNH

CH3

O H

N

H

H

HO

C

O

CH3

H N

H

H

HO

C

O

CH3

H

• Arrows move in a way that preserves bonding rules (e.g., 4 bonds to neutral C)

As a result of these two rules, arrows that start or end at atoms versus bonds refer todifferent pairs of electrons; it is therefore crucial that these arrows are drawn precisely. Whenan arrow starts at an atom it represents the movement of a lone pair of electrons on that atom(for example, the blue arrow in the top example above). When an arrow starts in the center ofa bond, in contrast, it represents the two electrons that make up the covalent bond.Movement of these electrons of course results in the breaking of that bond (for example, thered arrow in the top example).

The fate of these electron pairs set in motion is revealed by where an arrow ends.Terminating an arrow at an atom refers to the formation of a new covalent bond with thatatom (for example, the blue arrows in both examples above). When an arrow starts at a bondconnected to an atom and ends at the same atom, however, the meaning is that an electronpair is moving from a covalent bond to become a new lone pair associated with that atom (forexample, the first red arrow in both examples).

In contrast, ending an arrow at an existing bond signifies that an additional covalent bondis forming between the two atoms connected by the existing bond. If the existing bond is asingle bond, the result is the formation of a double bond. For example, the second red arrowin the bottom example shows a lone pair on a negatively charged oxygen atom forming asecond covalent bond between that oxygen atom and a connected carbon atom. A carbonylgroup (C=O) results.

Carefully study every detail of the examples above until the movement of electrons andthe changes in bonding are clear to you. You should also understand why each of the chargesshown above agrees with our understanding of formal charges.


Lectures 2 & 3: An introduction to the molecules of life1. The molecules of life comprise macromolecules and small molecules2. Understanding the molecules of life: chemical structures and bonding

a. Connectivity versus conformationb. The nature of atomsc. Covalent bonding and formal chargesd. Ionic bondinge. Electronegativity and hydrogen bondsf. The bonding continuum and bond polarity

3. Organic molecules and how to draw thema. The molecules of life are organic moleculesb. The geometries of organic moleculesc. Drawing organic moleculesd. Understanding “arrow-pushing” notation

4. Stereochemistry and the molecules of lifea. Stereoisomers and enantiomersb. Drawing stereoisomersc. The tragedy of thalidomided. Geometric isomerse. The role of geometric isomers in vision

5. The molecular components of HIV


Stereochemistry and Its Depiction

O

HONH2

CH3

O

HONH2

CH3

O

HONH2

CH3

Alanine(a protein building block)

L-Alanine D-Alanine

Enantiomers

belowthe page

abovethe page

• Isomers: non-identical molecules with the same chemical formula (e.g., C5O5H10)• Stereoisomers: isomers with identical atomic connectivities• Enantiomers: two stereoisomers that are mirror images (enantios = opposite)

1. Stereochemistry and the molecules of life

Stereoisomers and enantiomers

Some isomers at first glance appear to be identical molecules, but in reality are not. Forexample, shown here are two different isomers of a protein building block called “alanine”. Ifyou examine these two isomers, called L-alanine and D-alanine, you will see that the atom-to-atom connectivities of the two isomers are identical. The molecules themselves, however, arenot identical— they are mirror images of each other and cannot be superimposed. Twomolecules that share identical atomic connectivities but are nevertheless not identical arecalled stereoisomers. Stereoisomers that are mirror images of each other are calledenantiomers (from enantios, Greek for “opposite”). Enantiomers share the same relationshipas the left and right members of a pair of gloves. Because mirror images of alanine are notsuperimposable, alanine is classified as a chiral molecule (from cheira, the Greek word for“hand”). Molecules that are not chiral are achiral.

Given that stereoisomers share a common atomic connectivity, special conventions areneeded to draw them in a way that unambiguously identifies their stereochemicalconfiguration, or stereochemistry. In addition to simple lines and atom labels, two new kindsof lines are used to distinguish different stereoisomers. When drawing chemical structures,scientists use a thick line (sometimes drawn as a solid wedge-shaped line) to indicate a bondthat extends above the plane of the paper. Likewise, a dashed line (sometimes drawn as adashed wedge) indicates a bond that extends below the plane of the paper. By adding a thirddimension of depth to the standard organic molecule drawings you have studied earlier, thisconvention can specify the stereochemistry of any molecule.


Rotate 180°(Same molecule)

Enantiomers of Alanine

L-Alanine D-Alanine

Mirror(Enantiomers)

Mirror(Enantiomers)

Rotate 180°(Same molecule)

• Enantiomers cannot be superimposed

Note that, as before, hydrogen atoms are often not drawn explicitly to avoid excessiveclutter. By always keeping in mind the tetrahedral geometry of carbon atoms that make foursingle bonds, you can always infer where this implicit hydrogen atom should lie relative to theother three groups based on a correctly drawn molecule.

A quick test to determine if a molecule is chiral is to look for an atom (most often carbon)that is bonded to four different groups. Such an atom is called a chiral center, and itspresence in a molecule almost always indicates that the molecule is chiral. In the case ofalanine, the central carbon atom is bonded to (i) a –H group, (ii) a –CH3 group, (iii) a –COOHgroup, and (iv) a –NH2 group. Because all four of these groups are different, alanine is a chiralmolecule and its central carbon atom is a chiral center. We will see additional examples ofchirality in biological molecules and its consequences throughout this course.


Chiral Centers and Chiral Molecules

Not superimposable

Chiral

Enantiomers

Superimposable

Achiral

Identical structures

chiral center

• An atom attached to four different groups is a chiral center (asymmetric carbon)• A molecule is chiral if it cannot be superimposed on its mirror image• All chiral molecules contain at least one chiral center• A chiral center usually (but not always) indicates that a molecule is chiral

Four different groups

As you might imagine, enantiomers share many chemical properties. Enantiomers have thesame chemical formula, the same molecular weight, the same boiling point, the same meltingpoint, and under regular sunlight have the same physical appearance. In fact, enantiomerscannot be distinguished by any test that does not use a chiral probe such as a chiral moleculeor a special light source called plane-polarized light. However, when a chiral probe isinterfaced with a chiral molecule, the resulting interactions are different depending on whetherthe “left-handed” or “right-handed” enantiomer of the chiral molecule is used. Sometimes thechiral probe will interface with the chiral molecule like a left-hand fitting a left-handed glove. Ifyou tried to interface a left hand with a right-handed glove, however, the fit would be poor atbest. In this example, the left hand can be used to distinguish a left-handed glove from aright-handed glove— two objects that have an enantiomeric relationship.


Small Molecule-MacromoleculeInteractions are Sensitive to Chirality

Enantiomers of a drug

Binding site in a protein Binding site in a protein

• Enantiomers have identical basic properties (boiling point, melting point, color)• In the presence of a chiral probe (e.g., a protein), enantiomers behave differently

The vast majority of the macromolecules and small molecules underlying life are chiral.Based on your understanding of stereochemistry and chiral molecules, you may already realizethat this fact implies that two enantiomers can interact in different ways with biologicalmolecules. As a result, enantiomers can have very different biological properties. As a simpleexample, L-alanine (the enantiomer found in natural proteins) is recognized and processed bythe cell during the course of many crucial life processes including the creation of proteins. Incontrast, D-alanine (the enantiomer of L-alanine) is not recognized by the cellular machineryand cannot participate in these processes.


Thalidomide: Enantiomers withDifferent Biological Effects

N

O

ONH

OO

chiral center

Thalidomide: one enantiomertreats morning sickness…

…but the other is apotent teratogen

The tragedy of thalidomide

A dramatic example of the ability of living systems to respond differently to enantiomers isthe tragedy of thalidomide. Thalidomide is a chiral small molecule that was widely prescribedto pregnant women between 1957 and 1962 as a sedative and as a drug to relieve morningsickness. It was later discovered that only one enantiomer of thalidomide is responsible for itsbeneficial effects. The other enantiomer is a potent teratogen, inducing devastating physicaldefects in developing fetuses. Thalidomide was originally manufactured as an equal mixture ofboth enantiomers (such a mixture is called a racemate). Approximately 15,000 fetusesworldwide were damaged by the toxic enantiomer of thalidomide. Twelve thousand of thesefetuses survived to give rise to newborns with birth defects, of which 8,000 survived past thefirst year; most of these so-called “thalidomide children” are still alive but many suffer fromdebilitating deformities. Subsequent studies revealed that the two enantiomers of thalidomidecould interconvert in humans, and therefore even treating pregnant women with only thebeneficial enantiomer of the drug could still lead to birth defects. Fortunately for Americans,the newest FDA reviewer in 1960, Frances Kelsey, refused to approve thalidomide for use inthe U.S., probably preventing thousands of birth defects. This decision would earn Kelsey thePresident's Award for Distinguished Federal Civilian Service (at the time, the highest civilianaward in the U.S.) in 1962 presented by President John F. Kennedy.


N

S

O

HNH

R

O

OOH

O

HO

Stereoisomers of Modern Drugs

OO OH

IbuprofenBoth enantiomers effective;

one works slightly faster

PenicillinOne stereoisomer is effective;

others are not effective butnon-toxic

KetoprofenOne enantiomer relieves painand inflammation; the other

prevents tooth disease!

Even though living systems are full of chiral probes in the form of chiral macromoleculesand chiral small molecules, not all enantiomers of chiral drugs are toxic. In fact, mostenantiomers of drugs are either similar in their activity (such as ibuprofin, the active ingredientof Advil), or are ineffective yet are not toxic (such as penicillin). Still, the stereoisomers ofthalidomide serve as a potent reminder of the profound importance of stereochemistry in livingsystems.


H

H

Geometric Isomers

H

H

H

H

H H

trans-2-pentenecis-2-pentene

Ethylene is planar and double bondscannot easily be twisted

• When groups attached to each double-bonded carbon atom are different,geometric isomers are possible (cis = Latin for “on this side”, trans = “across”)

• Cis and trans isomers cannot interconvert without breaking the C=C double bond

Geometric isomers

To illustrate a different kind of stereoisomerism, let’s take another look at the carbon-carbon double bond. We learned that the six atoms in ethylene (H2C=CH2) all lie on the sameplane in order to satisfy the geometric requirements for the electron clouds that make updouble bonds. The six-atom coplanarity of carbon-carbon double bonds has some importantimplications for the molecules of life. When each carbon atom participating in a carbon-carbondouble bond make single bonds to two different groups, the resulting molecule can exist asone of two stereoisomers. For example, in this molecule called 2-pentene each trigonal carbonatom makes single bonds to two distinct groups: the trigonal carbon on the left is connected toa hydrogen and a –CH3 group; likewise, the trigonal carbon on the right is connected to ahydrogen and a –CH2CH3 group. We can draw 2-pentene either to place the –CH3 and–CH2CH3 groups on the same side of the double bond, or on different sides. When the groupsare on the same side of the double bond, the resulting structure is called the cis isomer (cis isLatin for “on this side”); when the groups are on opposite sides, the resulting structure iscalled the trans isomer (trans is Latin for “across”). Because the carbon-carbon double bond in2-pentene is planar, cis-2-pentene and trans-2-pentene cannot interconvert without breakingthe carbon-carbon double bond. Breaking this double bond requires a considerable amount ofenergy, and therefore both cis-2-pentene and trans-2-pentene are stable under mostconditions.


Retinal: Geometric Isomers in Vision

11-cis-retinal 11-trans-retinal

cis trans

Light

Light

Molecules that differ in the cis/trans geometry of one or more double bonds but that areotherwise identical are geometric isomers. Geometric isomers are a subset of stereoisomers inthat their atom-to-atom connectivities are identical. Unlike enantiomers, however, geometricisomers do not require a chiral probe to exhibit different behavior. Indeed, the basic physicalproperties of geometric isomers including their physical lengths, boiling points, meltingtemperatures, and colors are often different.

The role of geometric isomers in vision

A striking example of life exploiting the different properties of geometric isomers is themolecular basis of vision in animals. Examine the structure of 11-cis-retinal, a molecule that ismade by your body from vitamin A, stored in your liver, and transported to the retinas in youreyes. You can see that 11-cis-retinal contains several carbon-carbon double bonds. As itsname implies, the double bond connected to carbon #11 in this structure exists in the cisgeometry. When a photon of visible light collides with 11-cis-retinal, the cis carbon-carbondouble bond at this position can temporarily break and reform in the trans configuration. As aresult of this geometric change, or isomerization, the shape and length of retinal changes inresponse to visible light.


Rhodopsin: A Protein &Small Molecule Team

• The cis-trans isomerization of retinalchanges the conformation andfunction of rhodopsin, initiating thesignaling cascade driving vision

cis-retinal covalentlybound to opsin

In your retina, retinal is covalently bonded with a protein called opsin. Together, the small-molecule/protein pair is known as rhodopsin. When the 11-cis-retinal group in rhodopsinundergoes isomerization to trans-retinal, the resulting change in the shape and length of theretinal induces conformational changes in the protein. These changes in turn initiate a cascadeof molecular changes eventually (and very rapidly) resulting in your ability to see. Humanvision will be explored more extensively in Life Sciences 1b next semester.


Molecular Componentsof HIV

RNA

Protein

Lipid

4. The molecular components of HIV: a preview

Armed with a basic understanding of the structure of atoms and molecules, the ways inwhich atoms can form chemical bonds, the special features of organic molecules, the commonmethods of drawing molecules, and the importance of stereochemistry, we are now ready totake a chemical look at the key macromolecules of life: nucleic acids, proteins, and lipids. Inthe remainder of the first half of this course, we will continually return to HIV as a unifyingframework to understand how the chemical properties of these molecules of life enable theirbiological roles.

HIV is an ideal target for such an analysis because of its simplicity. In fact HIV is so simplethat, despite its devastating ability to take over human cells and to replicate, most scientistswould not consider HIV to be a form of life. Nevertheless, HIV does contain each of the majorclasses of biological molecules, and their collective biological roles are all necessary for HIV toinfect cells and to reproduce. We will end this lecture with a brief overview of the molecularcomponents of HIV.

The outside layer of an HIV virus is a membrane of molecules called lipids that contain long,greasy carbon and hydrogen (hydrocarbon) tails and charged head groups. This lipid envelopecontains proteins that enable HIV to attach to the surfaces of a certain type of human cellcalled T-cells. Ironically, T-cells are a major component of the human immune system andnormally protect human cells from foreign invaders. We will discuss in detail the chemistry andbiology of lipids later in this course.


Key Points: An Introduction to theMolecules of Life

• The molecules of life are macromolecules and small molecules• Covalent bonds arise from shared valence electrons and define

the connectivity of a molecule• Ionic and hydrogen bonds arise from electrostatics• Organic molecules contain carbon atoms in one of three

geometries, and are drawn in a standard convention using lines

• Reaction mechanisms are described by “arrow pushing”• Chiral molecules are not superimposable with their mirror

images (they exist as enantiomers)• Enantiomers have different properties in a chiral setting

• Geometric isomers (cis vs. trans C=C) have distinct properties

[From the previous slide] Beneath the lipid envelope are two coats of protein. The proteinin the outer coat has several names, including Gag, p17, and the HIV matrix protein. Theprotein in the inner coat is called the core antigen capsid protein, or p24 and surrounds thecore of the virus. Both Gag and p24 not only serve structural roles, but also facilitate severalof the key steps in the HIV life cycle.

Within the p24-covered core of the virus are several essential HIV proteins that catalyze keychemical reactions necessary for HIV infection and propagation. Two of these proteins, HIVreverse transcriptase and HIV protease, are major targets of AIDS drugs. The latter proteinwill be discussed in great detail later in this course. The core of HIV also contains two copiesof the molecular blueprint of HIV, a strand of RNA that contains all of the instructionsnecessary to take over a human T-cell and transform it into a factory for making thousands ofcopies of the HIV virus.

In the next several lectures we will examine in detail the chemistry and biology of each ofthe macromolecules of life, beginning with nucleic acids.

professor david liu and brian tse, life sciences 1a page...

Documents