Chapters 1-5 Practice Flashcards

Introduction to Biochemistry and the Protein-Folding Problem

Biochemistry is the study of chemical reactions occurring within biological molecules. The sum total of these reactions constitutes metabolism. Despite the potential for astronomical complexity, metabolism is streamlined; for instance, only 20 common amino acids are utilized to build proteins, enabling efficient control. A fundamental tenet of biochemistry is the inextricable link between molecular structure and biological function.

Historically, the study of protein structure reached a milestone in 1962 when John Kendrew and Max Perutz received the Nobel Prize for determining the three-dimensional structures of myoglobin and haemoglobin. This work paved the way for the contemporary 'protein-folding problem,' which seeks to discover the rules by which a protein's primary sequence determines its precise three-dimensional shape. Understanding this is vital because faulty folding is linked to diseases such as Alzheimer’s, Parkinson’s, and cystic fibrosis.

Modern solutions involve Artificial Intelligence (AI). Deep Blue's 1997 victory over Garry Kasparov was an AI milestone, but recent developments like AlphaZero (created by Demis Hassabis) and AlphaFold use reinforcement learning to tackle biological complexity. In 2018, AlphaFold significantly improved the accuracy of protein structure prediction. These technologies hold the potential to design more effective drugs and analyze complex global issues like climate change.

The Building Blocks of Life: Monomers and Polymers

The four most abundant elements in living organisms are hydrogen, carbon, oxygen, and nitrogen, accounting for over $99\%$ of all atoms. Carbon is the essential skeleton for organic molecules due to its ability to form long chains and rings. Simple biological molecules serve as building blocks for complex macromolecules. There are three primary types of macromolecules: polysaccharides, proteins (polypeptides), and nucleic acids (polynucleotides).

Macromolecules are typically polymers, which are giant molecules made of many similar repeating subunits called monomers. These monomers are joined by strong covalent bonds through a process called condensation. A condensation reaction involves the joining of two molecules with the simultaneous removal of a water molecule ( $H_{2}O$ ). Conversely, polymers are broken down through hydrolysis, where a covalent bond is cleaved by the addition of water. Monomers include monosaccharides for polysaccharides, amino acids for proteins, and nucleotides for nucleic acids.

Carbohydrates: Structure and Function

Carbohydrates consist of carbon, hydrogen, and oxygen in a ratio of approximately $C_{x}(H_{2}O)_{y}$ . They are categorized into monosaccharides, disaccharides, and polysaccharides. Monosaccharides are sweet, water-soluble sugars with the general formula $(CH_{2}O)_{n}$ . They are classified by carbon count: trioses ( $3C$ ), pentoses ( $5C$ ), and hexoses ( $6C$ ). Common hexoses include glucose, fructose, and galactose.

Glucose ( $C_{6}H_{12}O_{6}$ ) is the most common monosaccharide. In solution, it forms a stable ring where carbon 1 joins the oxygen on carbon 5. It exists as two isomers: $\alpha$ -glucose (hydroxyl group on C1 is below the ring) and $\beta$ -glucose (hydroxyl group on C1 is above the ring). Monosaccharides serve as energy sources (rich in $C-H$ bonds for ATP production) and building blocks (e.g., ribose in RNA and ATP; deoxyribose in DNA).

Disaccharides form when two monosaccharides join via a glycosidic bond (a $C-O-C$ link). Common examples include maltose ( $glucose + glucose$ ), sucrose ( $glucose + fructose$ ), and lactose ( $glucose + galactose$ ). Sucrose is the non-reducing transport sugar in plants, while lactose is found in milk. Sugars are tested using Benedict's reagent (alkaline copper(II) sulphate). Reducing sugars reduce blue $Cu^{2+}$ to a brick-red $Cu^{+}$ precipitate. Non-reducing sugars (sucrose) require acid hydrolysis and neutralization before testing.

Polysaccharides are long chains of monosaccharides. Starch (plant storage) is a mixture of amylose (unbranched $1,4$ linked $\alpha$ -glucose coiling into a helix) and amylopectin (short $1,4$ chains with $1,6$ branches). Glycogen is the animal storage equivalent, similar to amylopectin but more highly branched, stored as granules in liver and muscle cells. Cellulose is a structural polysaccharide in plant cell walls made of $\beta$ -glucose. Successive units are rotated $180^{\circ}$ to form straight chains. These chains cross-link via hydrogen bonds to form microfibrils and then fibres, providing high tensile strength to withstand osmotic pressure.

Lipids: Triglycerides and Phospholipids

Lipids are diverse organic molecules insoluble in water. Triglycerides are formed from one glycerol molecule and three fatty acids via condensation, creating three ester bonds ( $-COO-$ ). They are non-polar and hydrophobic, serving as energy stores (higher calorific value than carbohydrates), insulators (subcutaneous fat), and sources of metabolic water (crucial for desert animals like the kangaroo rat).

Fatty acids have a carboxyl group ( $-COOH$ ) head and a hydrocarbon tail. Saturated fatty acids have no double bonds, while unsaturated fatty acids contain one (monounsaturated) or more (polyunsaturated) double bonds, creating 'kinks' that make them liquid at room temperature (oils). Phospholipids are specialized lipids where one fatty acid is replaced by a polar phosphate group. This creates a hydrophilic head and two hydrophobic tails, allowing them to form the foundation of cell membranes.

Proteins: Structure, Folding, and Varieties

Proteins constitute over $50\%$ of the dry mass of most cells and perform diverse roles: enzymes, hormones (insulin), pigments (haemoglobin), antibodies, and structural components (collagen, keratin). They are polymers of amino acids. All amino acids share a central carbon, an amino group ( $-NH_{2}$ ), a carboxyl group ( $-COOH$ ), a hydrogen atom, and a variable R-group. Amino acids link via peptide bonds ( $C-N$ link) formed through condensation.

Protein structure is hierarchical:

Primary Structure: The specific sequence of amino acids in a polypeptide chain.
Secondary Structure: Regular coiling or folding held by hydrogen bonds between $C=O$ and $-NH$ groups, forming an $\alpha$ -helix or $\beta$ -pleated sheet.
Tertiary Structure: The complex three-dimensional folding of the chain, maintained by four bond types: hydrogen bonds (between polar R-groups), disulphide bonds (strong covalent bonds between cysteine R-groups), ionic bonds (between charged R-groups), and hydrophobic interactions (non-polar R-groups clustering away from water).
Quaternary Structure: The arrangement of multiple polypeptide chains (and sometimes prosthetic groups) into a functional unit.

Globular proteins (e.g., haemoglobin, enzymes) are spherical and water-soluble because hydrophilic R-groups face outward. Haemoglobin consists of two $\alpha$ -chains, two $\beta$ -chains, and four iron-containing haem prosthetic groups for oxygen transport. Sickle cell anaemia results from a single amino acid substitution (glutamic acid to valine) on the $\beta$ -chain surface, reducing solubility. Fibrous proteins (e.g., keratin, collagen) are long, insoluble strands with structural roles.

Nucleic Acids: DNA and RNA

Nucleic acids serve as the genetic material. DNA (deoxyribonucleic acid) stores information and replicates accurately. Nucleotides consist of a nitrogenous base, a pentose sugar, and a phosphate group. In DNA, the bases are Adenine (A), Guanine (G) (purines - two rings), and Cytosine (C), Thymine (T) (pyrimidines - one ring). In RNA, Uracil (U) replaces Thymine.

Two nucleotides join by a phosphodiester bond to form a dinucleotide. DNA is a double helix composed of two antiparallel polynucleotide strands running in $5'$ to $3'$ and $3'$ to $5'$ directions. Strands are held by hydrogen bonds between complementary base pairs: A pairs with T ( $2$ bonds), and G pairs with C ( $3$ bonds). This structure, discovered by Watson, Crick, and Franklin, allows for information storage (base sequence) and replication (unzipping to act as templates).

RNA (ribonucleic acid) is typically single-stranded and shorter-lived. There are three types:

Messenger RNA (mRNA): Transcribes genetic code from DNA to act as a template for protein synthesis.
Ribosomal RNA (rRNA): The most abundant type, forming the structure of ribosomes.
Transfer RNA (tRNA): Small, clover-leaf shaped molecules that carry specific amino acids to the ribosome; they contain an anticodon triplet and an acceptor end ( $CCA$ ).

Enzyme Mode of Action and Kinetics

Enzymes are globular protein catalysts that lower activation energy ( $E_{a}$ )—the energy required for a reaction to occur. They possess an active site to which a specific substrate binds, forming an enzyme-substrate complex. The 'lock-and-key' hypothesis suggests exact complementary shapes, while the 'induced-fit' hypothesis suggests the enzyme changes shape slightly for a perfect fit, increasing catalytic efficiency. Enzymes can be intracellular (respiration) or extracellular (digestive enzymes).

Enzyme activity is influenced by several factors:

Temperature: Activity increases with kinetic energy until the optimum. Beyond this, vibrations break hydrogen bonds, causing denaturation and loss of active site shape.
pH: Deviations from the optimum pH affect the ionization of R-groups, disrupting ionic bonds and changing active site shape.
Concentration: Increasing enzyme or substrate concentration increases the reaction rate until a limiting factor is reached. At maximum substrate saturation, the reaction reaches its maximum velocity, $V_{max}$ .

The Michaelis-Menten constant ( $K_{m}$ ) is the substrate concentration at which the reaction rate is half of $V_{max}$ ( $\frac{1}{2}V_{max}$ ). A low $K_{m}$ indicates a high affinity for the substrate, meaning the enzyme works efficiently at low concentrations.

Enzyme Inhibition and Industrial Applications

Inhibitors reduce enzyme activity. Competitive inhibitors have shapes similar to the substrate and compete for the active site; their effect can be overcome by increasing substrate concentration. Non-competitive inhibitors bind elsewhere on the enzyme, altering its tertiary structure and active site; increasing substrate concentration does not overcome their effect. End-product inhibition is a form of negative feedback where the final product of a pathway inhibits an earlier enzyme.

Immobilized enzymes are fixed (e.g., in alginate beads), allowing for recycling, prevention of product contamination, and increased stability against temperature and pH changes. Industrial uses include:

Insulin production: Using genetically modified bacteria ( $E. coli$ ) in fermenters.
Penicillin: Produced via the fungus $Penicillium\,chrysogenum$ .
Mycoprotein: A sustainable protein source from $Fusarium\,venenatum$ .
Pectinase: Used in fruit juice clarification to hydrolyze pectin in cell walls.
Lactase: Producing lactose-free milk for intolerant consumers.

The Mammalian Gas Exchange System

Mammals require a specialized system to warm and clean air, maximize surface area for diffusion ( $70-75\,m^{2}$ ), and maintain concentration gradients. The pathway includes the trachea, bronchi, bronchioles, and alveoli ( $3 \times 10^{9}$ sacs).

Key structures and tissues include:

Cartilage: C-shaped rings in the trachea and irregular blocks in the bronchi prevent airway collapse.
Ciliated Epithelium and Goblet Cells: Goblet cells secrete sticky mucus (mucin) to trap particles; cilia beat to move the 'mucus escalator' to the throat.
Smooth Muscle: Found in bronchioles to regulate airflow through contraction and relaxation.
Elastic Fibres: Allow alveoli to stretch during inhalation and recoil during exhalation to expel air.
Squamous Epithelium: Extremely thin ( $25\,nm$ ) cells in alveolar walls to minimize diffusion distance.

Gas Transport and Respiratory Physiology

Oxygen is transported by haemoglobin ( $Hb$ ) within red blood cells ( $RBCs$ ). The oxygen dissociation curve is S-shaped because the binding of the first $O_{2}$ molecule distorts the protein shape, making subsequent binding easier (cooperative binding). In the lungs (high $pO_{2}$ ), $Hb$ is nearly $100\%$ saturated. In respiring tissues (low $pO_{2}$ ), it releases oxygen.

Carbon dioxide is transported in three ways: as hydrogencarbonate ions ( $85\%$ ), carbaminohaemoglobin ( $10%$ ), and dissolved in plasma ( $5\%$ ). Carbonic anhydrase catalyzes the formation of carbonic acid ( $H_{2}CO_{3}$ ), which dissociates into $H^{+}$ and $HCO_{3}^{-}$ .

Bohr Shift: High $pCO_{2}$ reduces $Hb$ 's affinity for oxygen, shifting the curve to the right and releasing more oxygen where it is needed.
Chloride Shift: To maintain ionic balance, $Cl^{-}$ ions move into $RBCs$ as $HCO_{3}^{-}$ ions diffuse out into the plasma.

Respiratory Disorders and Altitude Adaptation

Common disorders include:

Emphysema: Destruction of alveolar walls reduces surface area and elastic recoil, causing dyspnoea (shortness of breath).
Asthma: Chronic inflammation and constriction of bronchi triggered by allergens.
Bronchitis: Inflammation of the bronchi and excess mucus production, often due to infection or smoking.
Pneumonia: Infection causing alveoli to fill with fluid/pus.
Interstitial Lung Disease (ILD): Scarring of lung tissue (fibrosis) reducing elasticity.

At high altitudes, low atmospheric pressure leads to hypoxia. The body adapts through acclimatization: increased ventilation rate, increased secretion of erythropoietin ( $EPO$ ) from kidneys to stimulate red blood cell production (erythropoiesis), and increased capillary density in tissues.

The Human Circulatory System and Cardiac Cycle

Mammals have a closed, double circulatory system. The systemic circulation delivers blood to the body, while the pulmonary circulation goes to the lungs. Artery walls have three layers: an inner endothelium, a thick middle layer of smooth muscle and elastic fibres, and an outer collagen layer. Elastic arteries (like the aorta) stretch to dampen pressure surges; muscular arteries control blood distribution via vasoconstriction and vasodilation.

Capillaries are one-cell thick for exchange. Veins carry low-pressure blood and contain semilunar valves to prevent backflow. Blood consists of plasma (mostly water), red blood cells (biconcave, no nucleus), and various white blood cells (phagocytic neutrophils/monocytes and antibody-secreting lymphocytes).

Water's properties as a dipole allow for hydrogen bonding, giving it a high specific heat capacity and high heat of vaporisation, which helps in temperature buffering and cooling (sweating). Its solvent properties allow it to transport nutrients and metabolic wastes like urea.

The heart is a myogenic pump. The cardiac cycle involves:

Atrial Systole: Atria contract, pushing blood into ventricles.
Ventricular Systole: Ventricles contract; atrioventricular (bicuspid/tricuspid) valves shut ('lub' sound), and blood enters arteries.
Ventricular Diastole: Ventricles relax; semilunar valves shut ('dub' sound) to prevent backflow from arteries.

Heartbeat is coordinated by the Sinoatrial Node ( $SAN$ - pacemaker), which sends an excitation wave. The Atrioventricular Node ( $AVN$ ) delays the signal by $0.1\,s$ to allow atrial emptying before Purkinje fibres transmit the wave to the ventricle base for upward contraction.

Homeostasis: Principles and Osmoregulation

Homeostasis is the maintenance of a relatively constant internal environment (tissue fluid conditions). It relies on negative feedback loops: a receptor detects a change from the set point (stimulus), the control center (brain) processes the input, and an effector (muscle/gland) carries out a corrective action (output).

Osmoregulation is the control of the blood's water potential, monitored by osmoreceptors in the hypothalamus. If water potential is low, the posterior pituitary gland releases Antidiuretic Hormone ( $ADH$ ). $ADH$ binds to collecting duct cells in the kidney, triggering a signaling cascade (cAMP second messenger) that moves vesicles containing aquaporins to the cell surface membrane. This increases water reabsorption, resulting in small volumes of concentrated urine. If water potential is high, $ADH$ secretion stops, and aquaporins are removed.

Thermoregulation is managed by the hypothalamus. High body temperatures trigger vasodilation and sweating. Low temperatures trigger vasoconstriction, piloerection (hairs standing up to trap air), and shivering (thermogenesis via muscle contraction).

Blood glucose is regulated by the pancreas ( $70-110\,mg/100\,mL$ ). Insulin (from $\beta$ -cells) lowers glucose by promoting uptake and glycogenesis; glucagon (from $\alpha$ -cells) raises glucose via glycogenolysis. Blood pH ( $7.35-7.45$ ) is maintained by chemical buffers (bicarbonate), respiratory adjustment of $CO_{2}$ levels, and renal excretion of $H^{+}$ ions.

Questions & Discussion

Can you think of any potential problems with AI? AI might lead to privacy concerns, algorithmic bias, or a loss of human jobs. There are also ethical questions regarding how extensively AI should control medical decisions.

Do you think the benefits outweigh these problems, or not? Arguments for benefits include solving previously 'unsolvable' biological problems like protein folding and drug discovery, while arguments against emphasize the need for caution and human oversight.

Why is it important for the scientific community to work in collaboration for such breakthroughs? Complex problems like the DNA double helix (Watson, Crick, and Franklin) or modern AI research require immense diverse data and cross-disciplinary expertise (biology, physics, and computer science) that one person or lab cannot possess alone.

How does an inhaler help a patient with asthma? Inhalers typically contain bronchodilators that relax the smooth muscles around the bronchi, widening the airways to improve airflow and oxygen uptake during a constriction event.

Why does butter turn rancid if left unrefrigerated? In unsaturated lipids, double bonds can react with oxygen in the air (oxidation), especially at room temperature, leading to the breakdown of the molecule into smelly or toxic compounds.

Describe the symptoms of altitude sickness. Symptoms include headache, nausea, dizziness, and fatigue due to hypoxia. Severe cases can lead to pulmonary or cerebral edema ( $HAPE/HACE$ ).