The chemistry of life II: macromolecules

Cells build almost everything they need from four classes of large organic molecules: carbohydrates, lipids, proteins and nucleic acids. Three of them are polymers, long chains made by linking many similar small units called monomers. Learning how these molecules are built, and how their structure determines what they do, is the foundation for the rest of the course.

Building and breaking polymers

Cells assemble polymers by dehydration synthesis (also called a condensation reaction): two monomers are joined by a covalent bond, and a molecule of water is released. The reverse reaction, hydrolysis, uses water to break the bond. Digestion is mostly hydrolysis: enzymes in your gut break starch into glucose, proteins into amino acids and fats into fatty acids and glycerol. Building polymers costs energy, which the cell supplies from ATP (lesson 8); breaking them releases a little.

Carbohydrates: sugars and their polymers

Carbohydrates contain carbon, hydrogen and oxygen, usually in the ratio CH2O. The simplest are monosaccharides, single sugar units such as glucose, fructose and galactose (all C6H12O6, differing in arrangement) and the five-carbon sugars ribose and deoxyribose found in nucleic acids. In water, glucose exists mostly as a ring.

Two monosaccharides joined by a glycosidic bond form a disaccharide: sucrose (table sugar) is glucose plus fructose, and lactose (milk sugar) is glucose plus galactose. Many people lose the enzyme lactase after childhood and cannot break down lactose well, which is why lactose intolerance is common; in some populations with a long history of dairy farming, a genetic change keeps lactase active into adulthood.

Long chains of monosaccharides are polysaccharides. Small differences in how the units are linked produce very different materials:

Starch and cellulose are both made entirely of glucose, yet you can digest starch but not cellulose. The difference is the orientation of the glycosidic bond: alpha links in starch, beta links in cellulose. Human enzymes fit alpha links only. Cows and termites digest cellulose with the help of microbes in their guts that make cellulases. For us, cellulose is dietary fiber, which helps keep the gut working.

Carbohydrates also act as identity tags. Short sugar chains attached to proteins and lipids on the cell surface (glycoproteins and glycolipids) help cells recognize each other. The ABO blood groups, for example, are defined by small differences in sugar chains on red blood cells.

Lipids: fats, phospholipids and steroids

Lipids are a mixed group united by one property: they are mostly hydrophobic and do not dissolve well in water. They are not polymers in the strict sense, because they are not long chains of repeating units, but they are assembled from smaller parts.

Fats (triglycerides) consist of one glycerol molecule joined by ester bonds to three fatty acids. A fatty acid is a long hydrocarbon chain, usually 14 to 22 carbons, with a carboxyl group at one end. In a saturated fatty acid every carbon carries as many hydrogens as it can, with no double bonds, so the chains are straight and pack tightly; such fats, like butter, are solid at room temperature. Unsaturated fatty acids have one or more carbon–carbon double bonds, usually in the cis arrangement, which puts a kink in the chain. They pack loosely and form oils. Industrial partial hydrogenation once produced trans fats, which raise the risk of heart disease; Canada banned partially hydrogenated oils in foods in 2018, and the US Food and Drug Administration removed them from the list of ingredients generally recognized as safe in the same year.

Fats store energy densely: about 37 kJ per gram, compared with about 17 kJ per gram for carbohydrates and proteins. A person carries enough fat for weeks of energy, but only about a day's worth of glycogen.

Phospholipids are the main lipids of membranes. In a phospholipid, glycerol carries two fatty acids and a phosphate group linked to a small polar molecule such as choline. The result is amphipathic: a polar, charged head and two non-polar tails. In water, phospholipids spontaneously form a double layer, the lipid bilayer, with tails inside and heads facing the water. Lesson 6 develops this into the fluid mosaic model of membranes.

Steroids have a skeleton of four fused carbon rings. Cholesterol is a steroid found in animal membranes, where it adjusts fluidity, and it is the starting material for steroid hormones such as testosterone, estrogen and cortisol. Plants use similar molecules called phytosterols.

Proteins: the workers of the cell

Proteins do most of the work in cells. Enzymes speed up reactions; transporters and channels move substances across membranes; structural proteins such as collagen and keratin give strength; receptors and hormones carry signals; antibodies defend; motor proteins such as myosin produce movement. A typical human cell makes thousands of different proteins.

Every protein is a chain of amino acids. Each amino acid has a central carbon bonded to a hydrogen, an amino group, a carboxyl group and a variable side chain, called the R group. There are 20 standard amino acids, and their side chains differ in size, charge and polarity: some are non-polar (leucine, valine), some polar but uncharged (serine, glutamine), some acidic and negatively charged at pH 7 (aspartate, glutamate), and some basic and positively charged (lysine, arginine). The R groups give each protein its chemistry.

Amino acids join by peptide bonds between the carboxyl group of one and the amino group of the next, releasing water. A chain is called a polypeptide; it has an amino end (N-terminus) and a carboxyl end (C-terminus). A protein is one or more polypeptides folded into a specific shape. How the cell reads a gene to choose the order of amino acids is previewed in lesson 5 and developed in BIOL-207.

Four levels of protein structure

A protein's function depends on its three-dimensional shape, and that shape is usually determined by its amino acid sequence. Biochemists describe four levels of structure:

A single change in primary structure can change everything. In sickle cell disease, one amino acid in the beta chain of hemoglobin, glutamate (charged), is replaced by valine (non-polar). The non-polar patch makes hemoglobin molecules stick together when oxygen is low, deforming red blood cells into sickle shapes that block small blood vessels.

Heat, extreme pH, high salt or certain chemicals can disrupt the weak interactions that hold a protein's shape. The protein unfolds, or denatures, and loses its function. Cooking an egg denatures its proteins irreversibly. Fever is dangerous at very high temperatures partly because some proteins begin to lose their shape. In the cell, helper proteins called chaperones assist folding and refold damaged proteins; misfolded proteins that clump together are involved in diseases such as Alzheimer's and Parkinson's.

Predicting a protein's shape from its sequence was a famous unsolved problem for 50 years. In 2020 an artificial intelligence system, AlphaFold, predicted structures with accuracy close to experiment for many proteins, and its developers shared the 2024 Nobel Prize in Chemistry with David Baker, who designs new proteins. Experimental methods such as cryo-electron microscopy (lesson 4) remain essential for checking predictions and for structures the software gets wrong.

# Molecular mass of a short peptide from average residue masses (daltons)
residue = {"G": 57.05, "A": 71.08, "S": 87.08, "V": 99.13, "L": 113.16,
           "K": 128.17, "E": 129.12, "F": 147.18, "R": 156.19, "W": 186.21}
water = 18.02

def peptide_mass(seq):
    return sum(residue[a] for a in seq) + water   # add one water for the two chain ends

for seq in ["GAVL", "KLVFFAE", "RWEKLS"]:
    print(f"{seq:<8} {len(seq)} residues, {peptide_mass(seq):7.1f} Da")
print("A 300-residue protein is roughly", round(300 * 110 / 1000), "kDa")

GAVL     4 residues,   358.4 Da
KLVFFAE  7 residues,   853.0 Da
RWEKLS   6 residues,   817.9 Da
A 300-residue protein is roughly 33 kDa

A handy rule of thumb follows from the program: the average amino acid residue weighs about 110 daltons, so a protein of 300 amino acids weighs about 33 kilodaltons (kDa). Biologists use this constantly when they read the size of a protein band on a gel (lesson 4).

Nucleic acids: information molecules

Nucleic acids store and transmit genetic information. There are two kinds: deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Both are polymers of nucleotides. Each nucleotide has three parts: a five-carbon sugar (deoxyribose in DNA, ribose in RNA), a phosphate group, and a nitrogen-containing base. DNA uses the bases adenine (A), guanine (G), cytosine (C) and thymine (T); RNA uses uracil (U) in place of thymine.

Nucleotides link through phosphodiester bonds between the sugar of one and the phosphate of the next, forming a sugar–phosphate backbone with the bases sticking out. Each strand has a direction, written from the 5′ end to the 3′ end, named after carbon atoms in the sugar.

DNA is usually a double helix: two strands wound around each other, running in opposite directions, with bases paired in the middle by hydrogen bonds. A always pairs with T (two hydrogen bonds) and G with C (three hydrogen bonds). This complementary base pairing, worked out by James Watson and Francis Crick in 1953 using X-ray images made by Rosalind Franklin and Maurice Wilkins's group, explains how DNA is copied: each strand serves as a template for a new partner. RNA is usually single-stranded and folds on itself; it carries messages from genes to ribosomes and forms parts of the ribosome itself. Details of replication, transcription and translation belong to BIOL-207.

# Complementary strand and GC content
pair = {"A": "T", "T": "A", "G": "C", "C": "G"}

def reverse_complement(seq):
    return "".join(pair[b] for b in reversed(seq))

def gc_percent(seq):
    return 100 * sum(b in "GC" for b in seq) / len(seq)

s = "ATGCGTTA"
rc = reverse_complement(s)
print("strand:     5'-" + s + "-3'")
print("complement: 5'-" + rc + "-3'")
print("GC content:", gc_percent(s + rc), "%")

strand:     5'-ATGCGTTA-3'
complement: 5'-TAACGCAT-3'
GC content: 37.5 %

Nucleotides have other jobs too. ATP (adenosine triphosphate) is the cell's main short-term energy carrier (lesson 8). NAD+ and FAD carry electrons in metabolism (lessons 9 and 10). Cyclic AMP is a common signaling molecule inside cells (lesson 11).

Putting the four classes together

A useful habit is to ask, for any cell structure, which macromolecules it is made of. A membrane is a phospholipid bilayer with cholesterol, studded with proteins and decorated with carbohydrates. A ribosome is RNA plus protein. A chromosome is DNA wrapped around proteins. A plant cell wall is mostly cellulose. Muscle is largely protein. By the end of the course you should be able to describe any part of a cell in these chemical terms.