Chemical Foundations I

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1 Chemical Foundations I GBME, SKKU Molecular & Cell Biology H.F.K.

2 Chapter 2 Chemical Foundations 2.1 Covalent Bonds and Noncovalent Interactions 2.2 Chemical Building Blocks of Cells 2.3 Chemical Reactions and Chemical Equilibrium 2.4 Biochemical Energetics Knowledge from biochemistry

3 Why is it important? Draw your own cell! After learning MCB! All are molecules!!! Well-organized and well-structured Structures are informative itself!

5 Chemistry of life: four key concepts. Molecular complementarity enables proteins with complementary shapes and chemical properties to form biomolecular interactions. Small molecule building blocks form larger cellular structures and polymers such as DNA. Chemical reactions are reversible. K eq, the ratio of forward (k f ) and reverse (k r ) reaction rate constants, reflects the relative amounts of products and reactants at equilibrium. Energy driving many cellular activities reactions is derived from hydrolysis of the highenergy phosphoanhydride bond linking the b and g phosphates in the ATP molecule.

Small molecule building blocks form larger cellular structures and polymers such as DNA. Chemical reactions are reversible.

6 Chemistry of life: four key concepts. Molecular complementarity enables proteins with complementary shapes and chemical properties to form biomolecular interactions. Small molecule building blocks form larger cellular structures and polymers such as DNA. Chemical reactions are reversible. K eq, the ratio of forward (k f ) and reverse (k r ) reaction rate constants, reflects the relative amounts of products and reactants at equilibrium. Energy driving many cellular activities reactions is derived from hydrolysis of the highenergy phosphoanhydride bond linking the b and g phosphates in the ATP molecule.

7 Chemistry of life: four key concepts. Molecular complementarity enables proteins with complementary shapes and chemical properties to form biomolecular interactions. Small molecule building blocks form larger cellular structures and polymers such as DNA. Chemical reactions are reversible. K eq, the ratio of forward (k f ) and reverse (k r ) reaction rate constants, reflects the relative amounts of products and reactants at equilibrium. Energy driving many cellular activities reactions is derived from hydrolysis of the highenergy phosphoanhydride bond linking the b and g phosphates in the ATP molecule. You can see the several states of molecules.

8 Chemistry of life: four key concepts. Molecular complementarity enables proteins with complementary shapes and chemical properties to form biomolecular interactions. Small molecule building blocks form larger cellular structures and polymers such as DNA. Chemical reactions are reversible. K eq, the ratio of forward (k f ) and reverse (k r ) reaction rate constants, reflects the relative amounts of products and reactants at equilibrium. Energy driving many cellular activities reactions is derived from hydrolysis of the highenergy phosphoanhydride bond linking the b and g phosphates in the ATP molecule.

9 You can use the molecules based on knowledge of MCB! Viral capsid protein <ex> Self-assembly proteins

10 Viral capsid protein Understanding the mechanism & environment (Basic science) Application (Engineering)

11 How is it possible?

12 Chapter 2 Chemical Foundations 2.1 Covalent Bonds and Noncovalent Interactions Molecules: hydrophilic, hydrophobic, and amphipathic Covalent bonds: shared electron pairs arrange specific molecular geometries such as stereoisomers around asymmetric carbons; unequal electron sharing yields polar covalent bonds with partial charges; more stable than weaker noncovalent interactions Four types of biological noncovalent interactions: ionic bonds (electrostatic interactions), hydrogen bonds (nonbonding electron hydrogen attraction), van der Waals interactions (transient dipole interactions), and hydrophobic effect interactions (reduces contact with water) Molecular complementarity: fit between molecular shapes, charges, and other physical properties

13 Covalent interaction A covalent bond, also called a molecular bond, is a chemical bond that involves the sharing of electron pairs between atoms

14 Strong covalent bonds form by atoms sharing pairs of electrons in their outermost electron orbitals

15 Geometry of bonds when carbon is covalently linked to three or four other atoms Most stable!

16 Stereoisomers Although L- and D-stereoisomers of amino acids are chemically identical, only L amino acids are found in proteins. Organic reaction?!

Configuration The source of the D and L labels was the Latin words dexter (on the right) and laevus (on the left) R comes from rectus (right-handed) and S from sinister (left-handed) As shown,

17 Configuration The source of the D and L labels was the Latin words dexter (on the right) and laevus (on the left) R comes from rectus (right-handed) and S from sinister (left-handed) As shown, the assignments in modern notation are R and S, respectively. (Note: it will not always work out that D = R and L=S; this is an accident here.)

18 D & L form D: Deter right L: Levo - left See the real model!

21 Non-covalent interaction What s the force?

22 Water

23 Van der Waals force are the residual attractive or repulsive forces between molecules or atomic groups that do not arise from covalent bonds, nor ionic bonds. force between permanent dipoles (Keesom force) force between a permanent dipole and a corresponding induced dipole (Debye force) force between instantaneously induced dipoles (London dispersion force).

Hydrogen bond A hydrogen bond is the electrostatic attraction between two polar groups that occurs when a hydrogen (H) atom covalently bound to a highly

24 Hydrogen bond A hydrogen bond is the electrostatic attraction between two polar groups that occurs when a hydrogen (H) atom covalently bound to a highly electronegative atom such as nitrogen (N), oxygen (O), or fluorine (F) experiences the electrostatic field of another highly electronegative atom nearby.

26 Are the Van der Waals force & H-bond weak?

27 Gecko s foot

29 Gecko s foot & Wan der Waals force

30 Wan der Waals force & Robotics Biomimics!

32 Ionic bond

33 The polarity of the O=P double bond causes one of the P=O double bond electrons to accumulate around the O atom, giving it a negative charge, leaving the P atom with a positive charge. The actual H 3 PO 4 structure is a resonance hybrid intermediate between the two representations.

34 Electrostatic interactions of the oppositely charged ions of salt (NaCl) in crystals and in aqueous solution

35 Red (negative) and blue (positive) lines represent contours and density of charge Where is the covalent bonding?

36 Electrons are shared. Electrons are not shared.

37 Hydrophobic interaction What s the meaning? Example?

38 Schematic depiction of the hydrophobic effect

39 Complementary binding

40 Molecular complementarity permits tight protein bonding via multiple noncovalent interactions

41 2.1 Covalent Bonds and Noncovalent Interactions 2.2 Chemical Building Blocks of Cells 2.3 Chemical Reactions and Chemical Equilibrium 2.4 Biochemical Energetics

42 Macromolecule polymers of monomer subunits: proteins-amino acids; nucleic acids-nucleotides; polysaccharidesmonosaccharides Proteins: differences in size, shape, charge, hydrophobicity, and reactivity of the 20 common amino acid side chains determine protein chemical and structural properties Nucleic acids: purine A and G, and pyrimidine C, T (DNA), and U (RNA) nucleotide bases comprise DNA and RNA Polysaccharides: hexoses (glucose and others) linked by two types of bonds Membranes: amphipathic phospholipids with saturated or unsaturated tails associate noncovalently to form bilayer membrane structure

43 Overview of the cell s principal chemical building blocks What kind of bond? What kind of bond?

44 Amino acids

45 The 20 common amino acids used to build proteins

46 Histidine R group charge Histidine R group imadazole shifts from positively charged to uncharged in response to small changes in acidity of its environment. Activities of many proteins are modulated by shifts in environmental acidity (ph) through protonation or deprotonation of histidine side chains.

47 What is this bond?

48 Common modifications of amino acid side chains in proteins. Amino acid R groups can be modified by addition of various chemical groups (red) during or after synthesis of a polypeptide chain.

49 Nucleotides

50 This makes huge difference in stability! Common structure of nucleotides. (a) Adenosine 5ʹ-monophosphate (AMP), a nucleotide present in RNA. All five nucleotides used to make nucleic acids DNA and RNA have a common structure: a phosphate group linked by a phosphoester bond to the 5 C in a pentose (five-carbon) sugar, which also is linked through its 1 C to a base. (b) Pentoses: ribose in RNA and deoxyribose in DNA. Bases: purines adenine and guanine, and pyrimidines cytosine in both DNA and RNA; thymine only in DNA or uracil only in RNA

51 Chemical structures of the principal bases in nucleic acids. Bases: purines (pair of fused rings) adenine and guanine, and pyrimidines (single ring) cytosine in both DNA and RNA; thymine only in DNA or uracil only in RNA

52 Terminology of Nucleosides and Nucleotides

53 Pyrophosphate group

54 ATP Where is the pyrophosphate? Energy!!!!

55 Monosaccharides Monosaccharides are the simplest form of carbohydrates. They consist of one sugar and are usually colorless, water-soluble, crystalline solids.

56 Chemical groups in monosaccharides

57 Where is the aldehyde? Chemical structures of hexoses. All hexoses have the same chemical formula (C 6 H 12 O 6 ) and contain an aldehyde or a keto group. (a) D-glucose linear and ring forms are interconvertible by reaction of the aldehyde at carbon 1 with the hydroxyl on C5 or C4 the six-member ring pyranose form (right) predominates in biological systems. (b) In D-mannose and D-galactose, the configuration of the H (green) and OH (blue) bound to C2 or C4 differs from that in glucose. D-mannose and D-galactose exist primarily as pyranoses (six-member rings). Where is the Keto?

58 Simple question! How does the L-glucose look like? Please draw on your notebook.

59 Real model of Glucose Why and How? Complex structure

60 2 attack!

61 Pyranose ring conformation Most stable conformation is chairlike with nonring H and O bonds nearly perpendicular to the ring (a, axial) or nearly in the plane of the ring (e, equatorial).

62 Formation of the disaccharides lactose and sucrose. Glycosidic linkage forms when the anomeric carbon of one sugar molecule (in either the α or β conformation) is linked to a hydroxyl oxygen on another sugar molecule. Lactose (milk sugar) contains a β(1 4) glycosidic bond, which is not digested in lactose-intolerant individuals missing the lactase enzyme. Sucrose (table sugar made by plants) contains an α(1 2) bond. Glucose is stored in larger polysaccahrides glycogen in animals and starch in plants. Human digestive enzymes can hydrolyze the α glycosidic bonds in starch but not the β glycosidic bonds in cellulose. Bacteria in cow and termite guts can.

63 Lipid

65 Discuss with friends 1. During much of the "Age of Enlightenment" in eighteenth-century Europe, scientists toiled under the belief that living things and the inanimate world were fundamentally distinct forms of matter. Then in 1828, Friedrich Wohler showed that he could synthesize urea, a well-known waste product of animals, from the minerals silver isocyanate and ammonium chloride. "I can make urea without kidneys!" he is said to have remarked. Of Wohler's discovery the preeminent chemist Justus von Liebig wrote in 1837 that the "production of urea without the assistance of vital functions... must be considered one of the discoveries with which a new era in science has commenced." Slightly more than 100 years later, Stanley Miller discharged sparks into a mixture of H20, CH4, NH1, and H2 in an effort to simulate the chemical conditions of an ancient reducing earth atmosphere (the sparks mimicked lightning striking a primordial sea or "soup") and identified many biomolecules in the resulting mixture, including amino acids and carbohydrates. What do these experiments suggest about the nature of biomolecules and the relationship between organic (living) and inorganic (nonliving) matter? What do they suggest about the evolution of life? What do they indicate about the value of chemistry in understanding living things? 2. RNA is less stable than DNA. Explain two reasons in aspects of chemical reaction and enzyme and discuss how to safely handle the RNA in lab.

66 Chemical Foundations II GBME, SKKU Molecular & Cell Biology H.F.K.

67 2.1 Covalent Bonds and Noncovalent Interactions 2.2 Chemical Building Blocks of Cells 2.3 Chemical Reactions and Chemical Equilibrium 2.4 Biochemical Energetics

68 At any one time, several hundred different kinds of chemical reactions are occurring simultaneously in every cell, and many chemicals can, in principle, undergo multiple chemical reactions.

69 Chemical reactions: K eq =product/reactant ratio when forward and reverse rates are equal Cell linked reactions are at steady state not equilibrium Dissociation constant(k d ) is measure of noncovalent interactions ph (-log[h + ]): cytoplasm (ph ) but lower in some organelles (lysosome, ph 4.5) Acids release protons (H + ); base bind protons Biological system uses weak acid/base buffers to maintain ph in narrow ranges.

Keq is fixed value! Time dependence of the rates of a chemical reaction. The extent and rate at which chemical reactions proceed determine the chemical composition of cells.

70 Keq is fixed value! Time dependence of the rates of a chemical reaction. The extent and rate at which chemical reactions proceed determine the chemical composition of cells. Chemical reactions are reversible. Initial forward and reverse reaction rates depend on the initial concentrations of reactants and products. The net forward reaction rate slows as the concentration of reactants decreases; the net reverse reaction rate increases as the concentration of products increases. Equilibrium: rates of the forward and reverse reactions are equal, and the concentrations of reactants and products remain constant. Equilibrium constant (K eq ): ratio of product to reactant concentrations at equilibrium and ratio of forward to reverse rate constants; depends on temperature and pressure [standard conditions are 25 C and 1 atm]. A catalyst can increase reaction rate but has no effect on K eq.

71 Comparison of reactions at equilibrium and at steady state. Reactions in cells may be linked in pathways in which a product of one reaction is not simply reconverted via a reverse reaction to the reactants, so reaction never reaches equilibrium. (a) Test tube reaction (A B) eventually reaches equilibrium, at which the rates of the forward and reverse reactions are equal (reaction arrows of equal length). (b) In a steady state pathway, the product B is made from A and converted to C at equal rates, but the individual reversible reactions never reach equilibrium (unequal arrow lengths) and B concentration can be different from that at equilibrium.

72 Which factors?

73 Dissociation constant Receptor Ligand binding P + D PD [P][ DJ K - d- [PO ] Lower or higher, which means the tighter for binding? What s this mean? Biotin and avidin bind with a dissociation constant of roughly 10^ 15 M = 1 fm = nm.

74 Not so simple Macromolecules can have distinct binding sites for multiple ligands. A large macromolecule (e.g., a protein, blue) can have multiple distinct independent or interdependent binding sites (A C) as shown; each with distinct dissociation constants (K d A C) for binding three different binding partners (ligands A C).

75 ph H 2 0 H + OH At 25 C, [H+][OH l = M 2, so that in pure water, IH. ] = [OH-] = 10 M. 1 1 ph= - log[h ] = log[ :;-= log 7 = 7 H ] 10

76 Why do we know the ph? All organisms, organs and organelles are working in their proper ph conditions.

Higher proton ion? Some ph values for common solutions. H + and OH - are dissociation products of H 2 O and present in all aqueous solutions (pure water, ph 7).

77 Higher proton ion? Some ph values for common solutions. H + and OH - are dissociation products of H 2 O and present in all aqueous solutions (pure water, ph 7). The ph of an aqueous solution is the negative log of the hydrogen ion concentration. ph values for most intracellular (cytoplasm ) and extracellular biological fluids are near 7 and are carefully regulated to permit the proper functioning of cells, organelles, and cellular secretions. ph values of intracellular organelles may be 4.5 (lysosome). Stomach ph is 1-2. Changes in ph can regulate cellular activities.

78 Acid & Base An acid is any molecule, ion, or chemical group that tends to release a hydrogen ion (H ), such as hydrochloric acid (HCI) A base is any molecule, ion, or chemical group that readily combines with a H, such as the hydroxyl ion (OH-) If Acid is added to the solution, how is the ph changed? If Base is added to the solution, how is the ph changed?

79 Acid dissociation constant pka Molecules characters. Constant value

80 ph & pka A stands for acid. HA H + + A. Ka = [H+lfA ]/ [HA]. [A ] ph= pk. + log [HA] where pk 3 equals - log K,. Henderson-Hasselbalch equation pk, of any acid is equal to the ph at which half the molecules are dissociated and half are neutral. If HA = A-

81 [A ] ph= pk. + log [HA] where pk 3 equals - log K,. How about the concentrations at ph6.4? The relationship between ph, pk a, and the dissociation of an acid. Acids release H + ; bases combine with H +. pk a of any acid is the ph at which half the molecules are dissociated and half are neutral (undissociated).

82 pka Knowing the pka, of a molecule not only provides an important description of its properties but also allows us to exploit these properties to manipulate the acidity of an aqueous solution and to understand how biological systems control this critical characteristic of their aqueous fluids.

83 A good example is Buffer (ex) A living, actively metabolizing cell must maintain a constant ph in the cytoplasm of about BUT! Cells have a reservoir of weak bases and weak acids, called buffers!

84 Buffer If additional acid (or base) is added to a buffered solution whose ph is equal to the pka of the buffer, the ph of the solution changes, but it changes less than it would if the buffer had not been present. [A ] ph= pk. + log [HA] where pk 3 equals - log K,.

What happens? Base added & bind to H+ The titration curve of the buffer acetic acid (CH 3 COOH). Many cells maintain cytosolic ph at 7.2-7.

85 What happens? Base added & bind to H+ The titration curve of the buffer acetic acid (CH 3 COOH). Many cells maintain cytosolic ph at despite metabolism producing acids by buffering ph with a reservoir of weak acid and base buffers that bond and release H +. Buffering capacity depends on concentration of the buffer and the relationship between its pk a value and the ph. Buffers best in range 1 ph unit above to below pk a : Acetic acid 4.75 (pk a ) is 91 percent CH 3 COOH at ph 3.75 and 9 percent CH 3 COOH at ph 5.75.

86 All biological systems contain one or more buffers.

87 Three protons! The titration curve of phosphoric acid (H 3 PO 4 ), a common buffer in biological systems. This biologically ubiquitous and abundant molecule has three hydrogen atoms that dissociate with different pk a values that buffer in three ph ranges.

88 2.1 Covalent Bonds and Noncovalent Interactions 2.2 Chemical Building Blocks of Cells 2.3 Chemical Reactions and Chemical Equilibrium 2.4 Biochemical Energetics

89 Which one is easier?

90 DG: measure of reaction change in free energy; -DG reactions are thermodynamically favorable; +DG reactions are not free energy change DG 0 (-2.3 RTlog K eq ): calculated from reactants/products at equilibrium rate of reaction: depends on activation energy; lowered by a catalyst Ex. Enzymes!!!

91 Enzymes in the cell

92 DG: measure of reaction change in free energy; -DG reactions are thermodynamically favorable; +DG reactions are not free energy change DG 0 (-2.3 RTlog K eq ): calculated from reactants/products at equilibrium rate of reaction: depends on activation energy; lowered by a catalyst -DG reaction such as ATP hydrolysis to ADP + P i can drive coupled +DG reaction.

93 ATP!

94 Phosphoanhydride bond Each of the two phosphoanhydride bonds-phosphodiester (red) in ATP (top) has a high-energy ΔG ʹ of about 7.3 kcal/mol for hydrolysis, because of the high amount of energy necessary to form the covalent bond holding two negatively charged (repellant) phosphate groups together.

95 ATP! Stable or unstable in sense of energy?

96 Hydrolysis of adenosine triphosphate (ATP). Cells use energy derived from exergonic reactions such as hydrolysis of ATP to ADP + P i to drive coupled endergonic reactions. Each of the two phosphoanhydride bonds-phosphodiester (red) in ATP (top) has a high-energy ΔG ʹ of about 7.3 kcal/mol for hydrolysis, because of the high amount of energy necessary to form the covalent bond holding two negatively charged (repellant) phosphate groups together. Energy derived from hydrolysis of the terminal phosphoanhydride bond is used by proteins to drive many energyrequiring reactions in biological systems.

97 But!

99 Where does the energy come from? How to make the high energy-containing molecules?

100 DG: measure of reaction change in free energy; -DG reactions are thermodynamically favorable; +DG reactions are not free energy change DG 0 (-2.3 RTlog K eq ): calculated from reactants/products at equilibrium rate of reaction: depends on activation energy; lowered by a catalyst -DG reaction such as ATP hydrolysis to ADP + P i can drive coupled +DG reaction. sun light energy captured by photosynthesis is ultimate source of all cell energy coenzyme (NAD+, FAD) oxidation (loss of e - ) and reduction (gain of e - ) electron transfer stores and transfers cell energy You can learn this in biochemistry class

101 Glycolysis

102 To pyruvate

103 Kreb cycle

104

The electron-carrying coenzymes NAD + and FAD. (a) NAD + (nicotinamide adenine dinucleotide) is reduced to NADH by the addition of two electrons and one proton simultaneously.

105 The electron-carrying coenzymes NAD + and FAD. (a) NAD + (nicotinamide adenine dinucleotide) is reduced to NADH by the addition of two electrons and one proton simultaneously. The other proton is released into solution. (b) FAD (flavin adenine dinucleotide) is reduced to FADH 2 by the addition of two electrons and two protons. In a redox reaction, electrons move spontaneously toward atoms or molecules having more positive reduction potentials (measured in volts, V).

106 Kreb cycle products

107 Electron transport chain

108 Total inputs and ouputs

109

110 Discussion with friends 3. If the PH is not proper to living organisms (ex. too high or too low), what happens in molecules such as protein, lipid and nucleotide? Please explain with an example. 4. Derive the Henderson-Hasselbalch equation and discuss the meaning of equation.

111 Discuss with friends 1. During much of the "Age of Enlightenment" in eighteenth-century Europe, scientists toiled under the belief that living things and the inanimate world were fundamentally distinct forms of matter. Then in 1828, Friedrich Wohler showed that he could synthesize urea, a well-known waste product of animals, from the minerals silver isocyanate and ammonium chloride. "I can make urea without kidneys!" he is said to have remarked. Of Wohler's discovery the preeminent chemist Justus von Liebig wrote in 1837 that the "production of urea without the assistance of vital functions... must be considered one of the discoveries with which a new era in science has commenced." Slightly more than 100 years later, Stanley Miller discharged sparks into a mixture of H20, CH4, NH1, and H2 in an effort to simulate the chemical conditions of an ancient reducing earth atmosphere (the sparks mimicked lightning striking a primordial sea or "soup") and identified many biomolecules in the resulting mixture, including amino acids and carbohydrates. What do these experiments suggest about the nature of biomolecules and the relationship between organic (living) and inorganic (nonliving) matter? What do they suggest about the evolution of life? What do they indicate about the value of chemistry in understanding living things? 2. RNA is less stable than DNA. Explain two reasons in aspects of chemical reaction and enzyme and discuss how to safely handle the RNA in lab. 3. If the PH is not proper to living organisms (ex. too high or too low), what happens in molecules such as protein, lipid and nucleotide? Please explain with an example. 4. Derive the Henderson-Hasselbalch equation and discuss the meaning of equation.

Biomolecules. Energetics in biology. Biomolecules inside the cell

Biomolecules. Energetics in biology. Biomolecules inside the cell Biomolecules Energetics in biology Biomolecules inside the cell Energetics in biology The production of energy, its storage, and its use are central to the economy of the cell. Energy may be defined as