The Structure and Function of Large Biological Molecules

Overview: The Molecules of Life

Despite the rich complexity of life, the critically important large molecules of all living things—from bacteria to elephants—fall into four main classes: carbohydrates, lipids, proteins, and nucleic acids.
Three of these classes (carbohydrates, proteins, and nucleic acids) are called macromolecules due to their enormous size on the molecular scale.
A single protein may consist of thousands of atoms, forming a molecular colossus with a mass exceeding $100,000\,\text{daltons}$ .
Large biological molecules exhibit unique emergent properties arising from the orderly arrangement of their atoms, illustrating the principle that architecture explains function.

Macromolecules are Polymers, Built from Monomers (Concept 5.1)

Polymer Definition: A long molecule consisting of many similar or identical building blocks linked by covalent bonds, analogous to a train chain of cars (from Greek polys, many, and meris, part).
Monomer Definition: The repeating units that serve as the building blocks of a polymer; these are smaller molecules that may also have independent functions.
Three of the four classes of organic compounds are polymers: carbohydrates, proteins, and nucleic acids.

The Synthesis and Breakdown of Polymers

Dehydration Reaction: The chemical mechanism used to connect monomers. Two molecules are covalently bonded through the loss of a water molecule. - One monomer provides a hydroxyl group ( $-OH$ ) and the other provides a hydrogen ( $-H$ ). - This process is facilitated by enzymes, specialized macromolecules that speed up chemical reactions.
Hydrolysis: The disassembly of polymers into monomers (from Greek hydro, water, and lysis, break). - A water molecule is added; a hydrogen from the water attaches to one monomer, and a hydroxyl group attaches to the adjacent monomer. - Example: Digestion: Organic material in food consists of polymers too large for cells. Enzymes in the digestive tract speed up hydrolysis to release monomers for absorption. Cells then use dehydration reactions to reassemble these into new, specific polymers.

The Diversity of Polymers

Each cell has thousands of different macromolecules, varying between cell types, individuals, and species.
Basis of Diversity: Molecules are constructed from only $40$ to $50$ common monomers (with some rare exceptions).
The Alphabet Analogy: Diversity is achieved through the particular linear sequence of units, similar to building hundreds of thousands of words from $26$ letters. However, biological polymers are often much longer (e.g., proteins are typically hundreds of amino acids long, built from $20$ kinds of amino acids).

Carbohydrates: Fuel and Building Material (Concept 5.2)

Carbohydrates include sugars and polymers of sugars.

Sugars

Monosaccharides: Simple sugars with molecular formulas generally being multiples of the unit $\text{CH}<em>2\text{O}$ . - Glucose ( $C_6H</em>{12}O_6$ ): The most common monosaccharide and central to life's chemistry. - Trademarks: A carbonyl group ( $C=O$ ) and multiple hydroxyl groups ( $-OH$ ). - Classification: - Aldose (Aldehyde sugar): Carbonyl group is at the end of the skeleton (e.g., Glucose, Galactose, Ribose, Glyceraldehyde). - Ketose (Ketone sugar): Carbonyl group is within the skeleton (e.g., Fructose, Ribulose, Dihydroxyacetone). - Carbon Skeleton Size: Ranges from three to seven carbons. - Hexoses: Six carbons (Glucose, Fructose). - Trioses: Three carbons (Glyceraldehyde). - Pentoses: Five carbons (Ribose). - Spatial Arrangement: Diversity arises from the placement of parts around asymmetric carbons (e.g., Glucose and Galactose differ only in the placement of parts around one asymmetric carbon). - Structure: While often drawn linear, most sugars form rings in aqueous solutions. In glucose, carbon $1$ bonds to the oxygen on carbon $5$ .
Disaccharides: Two monosaccharides joined by a covalent glycosidic linkage via dehydration. - Maltose: Glucose + Glucose ( $1\text{-}4$ glycosidic linkage). - Sucrose (Table Sugar): Glucose + Fructose. Used by plants to transport carbs from leaves to roots. - Lactose (Milk Sugar): Glucose + Galactose.

Polysaccharides

Polymers of a few hundred to a few thousand monosaccharides.
Storage Polysaccharides: - Starch: A polymer of glucose monomers used by plants. Stored as granules within plastids (including chloroplasts). - Amylose: The simplest form of starch, unbranched. - Amylopectin: More complex, branched polymer with $1\text{-}6$ linkages at branch points. - Glycogen: Extensively branched glucose polymer used by animals (stored in liver and muscle cells). Stores are depleted in about a day in humans without replenishment.
Structural Polysaccharides: - Cellulose: The most abundant organic compound on Earth ( $10^{14}\,kg$ produced per year). Component of plant cell walls. - Difference from Starch: Based on two ring structures of glucose: Alpha ( $\alpha$ ) and Beta ( $\beta$ ). In starch, all monomers are $\alpha$ . In cellulose, all are $\beta$ , making every other monomer "upside down." - Shape: Cellulose is straight and unbranched. Hydroxyl groups hydrogen-bond with parallel molecules to form cable-like "microfibrils." - Digestion: Humans cannot digest cellulose (it functions as "insoluble fiber" that abrades the digestive tract to stimulate mucus). Some prokaryotes and fungi can digest it (e.g., in a cow's rumen or a termite's gut). - Chitin: Used by arthropods for exoskeletons and by fungi for cell walls. Similar to cellulose but contains a nitrogen-containing appendage on the glucose monomer.

Lipids: Diverse Hydrophobic Molecules (Concept 5.3)

Lipids do not include true polymers and are generally not big enough to be macromolecules. They are grouped by their hydrophobic behavior (mixing poorly with water).

Fats

Assembled from glycerol (a 3-carbon alcohol) and fatty acids.
Fatty Acid Structure: Carboxyl group attached to a long hydrocarbon chain (usually $16$ or $18$ carbons).
Triacylglycerol (Triglyceride): Three fatty acids linked to one glycerol by ester linkages (bond between hydroxyl and carboxyl group).
Saturated Fatty Acid: No double bonds between carbon atoms; saturated with hydrogen. Solid at room temperature (e.g., butter, lard).
Unsaturated Fatty Acid: One or more double bonds (usually cis), creating a "kink." Liquid at room temperature (e.g., vegetable oils).
Trans Fats: Produced by hydrogenating vegetable oils; contain trans double bonds. Significant contributors to atherosclerosis.
Function: Primary function is energy storage. One gram of fat stores more than twice the energy of a gram of starch. Adipose cells also cushion organs and provide insulation.

Phospholipids

Essential for cell membranes. Consist of glycerol attached to two fatty acids and a phosphate group (carrying a negative charge).
Amphipathic Nature: Hydrocarbon tails are hydrophobic; phosphate heads are hydrophilic.
Bilayer: In water, they self-assemble into double-layered structures, shielding tails from water. This forms the boundary between the cell and its environment.

Steroids

Lipids with a carbon skeleton of four fused rings.
Cholesterol: A crucial steroid in animals; a component of cell membranes and a precursor for other steroids (like vertebrate sex hormones). Synthesized in the liver.

Proteins: Structure and Function (Concept 5.4)

Proteins account for over $50\%$ of the dry mass of most cells and are instrumental in almost every organismal activity.
Enzymes: Act as catalysts, selectively speeding up chemical reactions without being consumed.

Polypeptides

Polymers of $20$ different amino acids. A protein is one or more polypeptides folded into a specific shape.
Amino Acid Structure: At the center is an asymmetric alpha ( $\alpha$ ) carbon. Four partners: an amino group, a carboxyl group, a hydrogen atom, and a variable R group (side chain).
R Group Properties: - Nonpolar: Hydrophobic. - Polar: Hydrophilic. - Acidic: Negatively charged (has a carboxyl group). - Basic: Positively charged (has an amino group).
Peptide Bonds: Covalent bonds formed by dehydration between the carboxyl group of one amino acid and the amino group of another. The chain has an N-terminus (amino end) and a C-terminus (carboxyl end).

Protein Structure and Folding

Four Levels of Structure: 1. Primary: The unique linear sequence of amino acids, determined by genetic information. 2. Secondary: Coils and folds resulting from hydrogen bonds between backbone constituents. - $\alpha$ helix: Delicate coil held by H-bonds every fourth amino acid. - $\beta$ pleated sheet: Two or more regions of backbone lying side-by-side connected by H-bonds. 3. Tertiary: Overall shape resulting from R group interactions (hydrophobic interactions, van der Waals forces, hydrogen bonds, ionic bonds, and covalent disulfide bridges between cysteine monomers). 4. Quaternary: Aggregation of two or more polypeptide subunits (e.g., Collagen, a triple helix; Hemoglobin, four subunits with iron-containing heme).
Sickle-Cell Disease: A single amino acid substitution (valine for glutamic acid) in hemoglobin causes the protein to crystallize into fibers, deforming red blood cells into a sickle shape.
Denaturation: Loss of a protein's native shape due to changes in pH, salt concentration, or temperature, rendering it biologically inactive.
Chaperonins: Protein complexes that provide a sheltered environment for new polypeptides to fold spontaneously.
Measurement: X-ray crystallography, NMR spectroscopy, and bioinformatics are used to determine 3-D structure.

Nucleic Acids: Hereditary Information (Concept 5.5)

Gene: Unit of inheritance that programs the amino acid sequence of a polypeptide. Consists of DNA.

Roles of Nucleic Acids

Deoxyribonucleic Acid (DNA): Provides directions for its own replication; directs RNA synthesis.
Ribonucleic Acid (RNA): Messenger RNA (mRNA) conveys genetic instructions from the nucleus to the cytoplasm to direct protein synthesis at ribosomes.
Flow of Information: $\text{DNA} \rightarrow \text{RNA} \rightarrow \text{Protein}$ .

The Structure of Nucleic Acids

Polymers are called polynucleotides, made of nucleotide monomers.
Nucleotide Parts: 1. Nitrogenous Base: - Pyrimidines: Single six-membered ring. Cytosine (C), Thymine (T, only in DNA), Uracil (U, only in RNA). - Purines: Six-membered ring fused to a five-membered ring. Adenine (A), Guanine (G). 2. Pentose Sugar: Ribose (in RNA) or Deoxyribose (in DNA). Deoxyribose lacks an oxygen atom on the $2'$ carbon. 3. Phosphate Group: Attached to the $5'$ carbon of the sugar.
Phosphodiester Linkage: Consists of a phosphate group linking the sugars of two nucleotides, creating a sugar-phosphate backbone with $5'$ and $3'$ ends.

The DNA Double Helix

Proposed by Watson and Crick in $1953$ .
Two polynucleotides spiral around an axis, running in opposite $5' \rightarrow 3'$ directions (antiparallel).
Base Pairing: - Adenine (A) pairs with Thymine (T). - Guanine (G) pairs with Cytosine (C).
The two strands are complementary, allowed for precise copying during cell division.

Questions & Discussion

Concept Check 5.1, Q2: How many water molecules are needed to completely hydrolyze a polymer ten monomers long? - Answer: Nine molecules.
Concept Check 5.2, Q2: Formula for maltose ( $\text{Glucose} + \text{Glucose}$ via dehydration)? - Calculation: $(C_6H_{12}O_6 \times 2) - H_2O = C_{12}H_{22}O_{11}$ .
Evaluation Q2: What is the formula for a polymer of ten glucose molecules? - Answer: $C_{60}H_{102}O_{51}$ (Subtracting $9$ water molecules from ten glucose units).
Inquiry (Roger Kornberg): The 2006 Nobel Prize was awarded for using X-ray crystallography to determine the 3-D shape of RNA polymerase II. The model suggested a region above DNA acts as a clamp to hold nucleic acids in place.