Macromolecules

Biological macromolecules are large molecules built by linking smaller monomers — and they are among the highest-yield topics on the MCAT, spanning both the Chem/Phys and Bio/Biochem sections. This chapter covers the four classes the AAMC expects you to know cold: proteins (amino acids, peptide bonds, the four levels of structure, enzymes and enzyme kinetics), carbohydrates, lipids, and nucleic acids.

Classification of Proteins

Proteins are polymers of α-amino acids joined by peptide bonds (–CO–NH–) formed by condensation between the –COOH of one amino acid and the –NH₂ of the next. There are 20 standard amino acids, encoded by the genetic code, and the precise sequence determines the protein's three-dimensional shape and biological function.

Amino acid structure & properties

Every standard amino acid has a central (α) carbon bonded to four groups: an amino group (–NH₂), a carboxyl group (–COOH), a hydrogen, and a variable R (side chain) that defines its identity and chemistry. With four different groups, the α-carbon is a chiral center (except glycine, whose R = H) — all amino acids in proteins are the L isomer.

• Zwitterion & pI: at physiological pH the amino group is protonated (–NH₃⁺) and the carboxyl is deprotonated (–COO⁻), giving a net-neutral zwitterion. The pH at which the molecule carries no net charge is its isoelectric point (pI). Below the pI it is net positive; above it, net negative — the basis of separation by electrophoresis and ion-exchange chromatography.
• Side-chain classes: nonpolar/hydrophobic (e.g. Ala, Val, Leu, Phe), polar uncharged (Ser, Thr, Cys, Asn, Gln), acidic/negative (Asp, Glu), and basic/positive (Lys, Arg, His). Hydrophobic residues tend to pack into the protein core; charged/polar ones face the aqueous exterior.
• Special residues: glycine (smallest, flexible), proline (rigid ring, disrupts helices), and cysteine (its –SH forms disulfide bridges).
• Essential amino acids cannot be synthesized by the body and must come from the diet.

Classification by structure

Primary structure

The linear sequence of amino acids joined by peptide bonds. Determined by the gene's mRNA. Sickle-cell anemia is a primary-structure mutation: glutamic acid → valine at position 6 of β-globin.

Secondary structure

Local folding into α-helix or β-pleated sheet, stabilized by hydrogen bonds between the C=O and N–H groups of the polypeptide backbone.

Tertiary structure

The overall 3-D fold of a single polypeptide chain, stabilized by hydrogen bonds, hydrophobic interactions, ionic bonds, and disulfide (–S–S–) bridges between cysteine residues.

Quaternary structure

Assembly of two or more polypeptide subunits into a functional protein. Hemoglobin (2α + 2β subunits with 4 heme groups) is the textbook example.

Classification by composition

• Simple proteins — yield only amino acids on hydrolysis (e.g. albumin, globulin, keratin).
• Conjugated proteins — contain a non-protein prosthetic group: glycoproteins (sugar), lipoproteins (lipid), nucleoproteins (nucleic acid), metalloproteins, hemoproteins (heme, e.g. hemoglobin).
• Derived proteins — products of partial hydrolysis or denaturation (proteoses, peptones, peptides).

Classification by shape

• Fibrous proteins — long, insoluble in water, structural roles. Examples: collagen (skin, tendon), keratin (hair, nails), elastin, fibroin (silk).
• Globular proteins — spherical, water-soluble, functional/dynamic roles. Examples: hemoglobin, enzymes, antibodies, insulin.

Enzymes as Biocatalyst

Enzymes are biological catalysts — almost all are globular proteins (a few are catalytic RNA, called ribozymes). They speed up biochemical reactions by lowering the activation energy without being consumed and without changing the overall position of equilibrium.

Models of enzyme action

• Lock-and-Key (Fischer, 1894): rigid active site precisely complementary to the substrate — explains specificity but not flexibility.
• Induced Fit (Koshland, 1958): the active site molds itself around the substrate on binding — the modern accepted view.

Michaelis–Menten kinetics (qualitative)

At low substrate concentration, rate rises almost linearly with [S]. As [S] increases, the rate plateaus at a maximum value V_max when every enzyme molecule is saturated. The substrate concentration at which rate = ½ V_max is called K_m (Michaelis constant) — a low K_m means high affinity for the substrate.

Factors affecting enzyme activity

• Temperature: rate roughly doubles every 10 °C up to an optimum (~37 °C in humans). Above the optimum the protein denatures — tertiary structure unfolds and activity is lost permanently.
• pH: each enzyme has an optimum pH (pepsin ~2, salivary amylase ~6.8, trypsin ~8). Extreme pH alters ionization of active-site residues and denatures the enzyme.
• Substrate concentration: rate ↑ with [S] until V_max.
• Enzyme concentration: directly proportional to rate (when [S] is in excess).
• Cofactors / coenzymes: required by many enzymes — metal ions (Mg²⁺, Zn²⁺) or organic molecules (NAD⁺, FAD, derived from vitamins).

Inhibition

Competitive inhibition

Inhibitor structurally resembles the substrate and binds the active site. Effect can be reversed by raising [S]. Apparent K_m rises; V_max unchanged. Example: malonate vs succinate at succinate dehydrogenase.

Non-competitive inhibition

Inhibitor binds an allosteric (different) site, distorting the active site. Cannot be reversed by adding more substrate. V_max drops; K_m unchanged. Example: heavy metals (Hg²⁺, Pb²⁺) on enzyme –SH groups.

Importance of Proteins

Proteins are the most functionally diverse biomolecules. Roughly 50 % of the dry mass of cells is protein, and almost every cellular activity depends on one.

Daily requirement and deficiency

An average adult needs ~0.8 g protein per kg body weight per day. Severe deficiency causes kwashiorkor (edema, swollen belly — protein deficiency with adequate calories) or marasmus (overall energy and protein deficiency, severe wasting).

Carbohydrates

Carbohydrates have the general formula (CH₂O)_n and serve as fuel, energy storage, and structure. Their monomers are monosaccharides (simple sugars such as glucose, fructose, galactose), which are polyhydroxy aldehydes (aldoses) or ketones (ketoses).

• Ring forms & anomers: in solution glucose cyclizes to a hemiacetal ring, creating a new stereocenter at the anomeric carbon — the α (OH down) and β (OH up) anomers, which interconvert by mutarotation.
• Glycosidic bonds: monosaccharides join by condensation (loss of H₂O) into disaccharides (maltose, sucrose, lactose) and polysaccharides.
• Key polysaccharides: starch and glycogen (α-glucose, energy storage in plants and animals) vs cellulose (β-glucose, structural; humans lack the enzyme to hydrolyze the β-1,4 linkage). The α vs β linkage is the whole difference — a favorite MCAT point.

Lipids

Lipids are defined by being largely hydrophobic (nonpolar), not by a shared monomer. Major classes:

• Triacylglycerols (fats/oils): glycerol + three fatty acids joined by ester bonds; the body's main energy store (~9 kcal/g, more than twice carbohydrate or protein). Saturated fatty acids have no C=C (pack tightly, solid); unsaturated ones have cis double bonds that kink the chain (liquid oils).
• Phospholipids: a glycerol backbone with two fatty-acid tails and a phosphate-containing head — amphipathic (polar head, nonpolar tails), so they self-assemble into the bilayer of cell membranes.
• Steroids: four fused rings; cholesterol modulates membrane fluidity and is the precursor of steroid hormones, bile salts, and vitamin D.

Nucleic Acids

DNA and RNA store and transmit genetic information. Their monomer is the nucleotide = a nitrogenous base + a pentose sugar + one or more phosphate groups.

• Bases: purines (adenine, guanine — two rings) and pyrimidines (cytosine, thymine in DNA, uracil in RNA — one ring). Complementary base pairing: A–T (2 H-bonds) and G–C (3 H-bonds); RNA uses A–U.
• Backbone: nucleotides link by phosphodiester bonds between the 3′-OH of one sugar and the 5′-phosphate of the next, giving directionality (5′→3′).
• DNA vs RNA: DNA is double-stranded with deoxyribose (2′-H); RNA is usually single-stranded with ribose (2′-OH), which makes RNA less stable.
• ATP (a ribonucleotide) is the cell's energy currency — energy is released by hydrolyzing its high-energy phosphoanhydride bonds.

Worked MCQs

Five MCQs that capture the high-yield testing patterns for this chapter. Read the explanation even when you get the answer right — it's where the deeper concept lives.

Quick Recap

• Amino acids: chiral (L) α-carbon with variable R group; exist as zwitterions, net-neutral at the pI.
• Proteins = polymers of α-amino acids joined by peptide (amide) bonds. Four levels: primary (sequence, covalent), secondary (α-helix / β-sheet, backbone H-bonds), tertiary (3-D fold, incl. –S–S–, hydrophobic, ionic), quaternary (multiple subunits, e.g. hemoglobin).
• Enzymes lower E_a (E + S ⇌ ES → E + P); do not change ΔH or equilibrium. K_m = [S] at ½ V_max (low K_m = high affinity). Competitive ↑ K_m, V_max same; non-competitive ↓ V_max, K_m same.
• Carbohydrates: monosaccharide monomers, glycosidic bonds; starch/glycogen (α-glucose, storage) vs cellulose (β-glucose, structural).
• Lipids: hydrophobic; triacylglycerols (ester bonds, energy store), amphipathic phospholipids (membrane bilayer), steroids (cholesterol).
• Nucleic acids: nucleotide monomers (base + sugar + phosphate), phosphodiester backbone; A–T (2 H-bonds), G–C (3 H-bonds); ATP = energy currency.
• All four classes are condensation polymers built by losing water and broken down by hydrolysis.