Amino Acids, Peptides & Proteins  -amino acid:

Amino Acids Are >500 naturally occurring amino acids identified in living organisms Humans synthesize 10 of the 20 they use. The other 10 are called essential amino acids.

Amino Acids, Peptides & Proteins Peptides & proteins: Derived from amino acids through peptide or amide bonds. The amine and acid ends of amino acids couple to form amide (peptide) bonds in peptides/proteins/enzymes. Proteins fold into well-defined structures. The hydrophobic residues segregate to the water-free interior, while the polar/charged residues favor the exterior.

Peptides: Coupling AAs Together Peptides & Proteins: Linear oligomers of the 20 amino acids Peptides ≤ 20 amino acids; Proteins > 20 amino acids Functions: 1. Catalysis - enzymes 2. Membrane channels 3. Structural support (boundaries) 4. Regulate metabolites (storage & transport) 5. Antibodies; cellular signaling (recognition & binding)

Aspartame Discovery story: In 1965 by Jim Schlatter working on discovering new treatments for gastric ulcers. Made a dipeptide intermediate, which he spilled on his hand Tested the dipeptide in coffee Aspartame 4 calories per gram 180 times sweeter than sugar

Aspartame: A Dipeptide Two main constituents: Phenylalanine Aspartic acid Goal: 1. Make the methyl ester of phenylalanine 2. Make a peptide (amide) bond between phenylalanine and aspartic acid Overall - two main steps to this synthesis

Dipeptides: Coupling of 2 AAs Consider the synthesis of the dipeptide val-ala (valine-alanine): Coupling of amino acids is an application of nucleophilic acyl substitution Issue of selectivity arises: val + ala  val-ala + ala-val + val-val + ala-ala A mixture of 4 possible amide products

Merrifield’s Solid-Phase Synthesis In order to get the desired peptide (val-ala), the appropriate NH 2 and CO 2 units must be joined. The selectivity is accomplished through the use of protecting groups. Merrifield’s approach: 1. Protect N-terminus of valine 2. Protect C-terminus of alanine 3. Couple valine and alanine 4. Deprotect to get dipeptide

Merrifield’s Solid-Phase Synthesis 1. Protection of valine’s N-terminus:

Merrifield’s Solid-Phase Synthesis 2. Protection of alanine’s C-terminus: Attach the C-terminus to a plastic bead (solid-phase synthesis!) Benefits of solid-phase: Ease of attachment Ease of removal; just filter away from product solution

Merrifield’s Solid-Phase Synthesis 3. Couple valine and alanine:

Merrifield’s Solid-Phase Synthesis 3. Deprotection of Fmoc & bead:

Proteins Amino acid polymers; when long enough, they fold back on themselves to create intricate, well-defined 3D structures The structure of a protein specifies its function. The AA sequence specifies its structure. The AA chain typically adopts regional sub-structures which sum together to deliver the overall structure of the protein. Forces/Factors that dictate protein folding: 1. Planarity of amide bonds 2. H-bonding 3. Hydrophobic interactions 4. Electrostatic Attraction 5. Disulfide linkages

Proteins 1. Planarity of amide bonds:

Proteins 2. H-bonding: H-bond worth ~ 5 kcal/mol H-bonds orient the chain

Proteins 3. Hydrophobic Interactions: Lots of hydrophobic interactions between Rs and H 2 O - unstable Protein folds to “clump” R groups together in the interior of protein to avoid H 2 O - very energetically favored

Proteins 4. Electrostatic Attraction:

Proteins 5. Disulfide Linkages: Covalent S-S Drastically alters shape Worth ~ 50 kcal/mol

Proteins Overall, these 5 structural/energetic features leads to the final 3D protein structure. However, predicting the structure from the amino acid sequence is still a challenge. Hierarchy of Structural Elements of Proteins 1. Primary structure: AA sequence 2. Secondary structure: discrete sub-structural elements (modules)  -helix &  -sheet  -helix: see board for depiction Note: 1. Internal H-bonding 2. The way the side chains line up AAs per turn  -sheet: see board for depiction Note: 1. Chain-to-chain H-bonding 2. Alternating (up-down, up-down) Pattern of R groups

Proteins Hierarchy of Structural Elements of Proteins 3. Teritary Structure: the individual secondary structural elements organized in 3D. See board for depiction. 4. Quaternary Structure: non-covalent complexation of different proteins.

Lipids Structurally diverse, derived from living organisms Functional theme is hydrophobicity - water avoiding due to long alkyl chains Often found at the interface of aqueous compartments 3 Major Classes of Lipids: 1. Fats and oils 2. Phospholipids 3. Cholesterol & derivatives (steroids)

Lipids 1. Fats & Oils Derived from glycerol and fatty acids: Weak intra- molecular attractive forces between chains

Lipids 1. Fats & Oils In order for a fat to melt, these weak dispersive forces must be broken. More contacts, the better the packing and the higher the m.p. of the fat Less contacts, worse packing of chains, the lower the m.p. Unsaturated Fats: Oils are polyunsaturated - lots of alkenes & have low mp due to less packing Butter has very little unsaturated & has higher mp

Lipids Soaps & Detergents Hydrolyzed fats A long chain carboxylate molecule:

Lipids Soaps & Detergents Grease & dirt get trapped in the interior. Micelle is H 2 O soluble so can wash out dirt. In H 2 O, forms a micelle.

Lipids 2. Phospholipids: Have hydrophobic and hydrophilic regions Forms membranes Precursors to prostaglandins

Lipids 2. Phospholipids: Forms membranes: self-organize at certain concentrations to form bilayers Membranes are largely impermeable to charged species that exist in biological environments. Cell membrane

Lipids 3. Cholesterol & Steroids Cholesterol: 27 carbons 4 rings 8 stereocenters Derived from terpenes Cholesterol is a precursor to several steroidal hormones: Testosterone (male hormone) Estrone (female hormone)

Lipids Cholesterol is a precursor to several steroidal hormones: Testosterone (male hormone) Estrone (female hormone) These hormones operate at the genetic level (turn genes on and off) to control biochemistry. They are recognized by specific protein receptors.

Antioxidants & Chocolate Antioxidants: Protect against cardiovascular disease, cancer and cataracts Thought to slow the effects of aging Chocolate: High levels of antioxidants - complex mixtures of phenolic comounds By weight, has higher concentration of antioxidants than red wine or Green tea 20x higher concentration of antioxidants than tomatoes Dark chocolate has more than 2x the level of antioxidants as milk chocolate. Side note: The main fatty acid in chocolate, stearic acid, does not appear to raise blood cholesterol levels the way other saturated fatty acids do.