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Survey of Biomolecules Part III: Amino Acids, Peptides, and Proteins Lecture Supplement: Take one handout from the stage Why Bother With Protein Structure? Structure controls function •Enzyme selectivity •Drug design •Many others Fundamental protein structure = amide polymer R H H O R H H N N N H H R H O H N N O R O H R H O n Repeating unit Amino Acids Basic building block of protein structure = amino acid •All have amine and carboxylic acid groups •All are primary amines (-NH2) except proline •Side chains attached to α-carbon vary •Most have S configuration at α-carbon, except glycine (R = H) •Amine + carboxylic acid = proton transfer possible R α-carbon H H OH R H O N N H O Neutral (unionized) form H H H Keq > at physiological pH O Zwitterionic (ionized) form Amino Acids The 21 natural amino acids categorized by side chain properties: •Hydrophilic versus hydrophobic •Acidic versus basic versus neither (nonacidic) Hydrophobic nonacidic side chains H H2N H3C H COOH Glycine (Gly) H2N H H H COOH H2N Alanine (Ala) H2N COOH Valine (Val) H COOH Leucine (Leu) H2N COOH Isoleucine (Ile) Achiral H N CH3S COOH H Proline (Pro) HN H H H2N COOH Tryptophan (Try) H2N H COOH Phenylalanine (Phe) H2N COOH Methionine (Met) 2o amine (HNR2) Amino Acids Hydrophobic acidic side chains HS HSe H H2N COOH Cysteine (Cys) H H2N COOH Selenocysteine (Sec) Rare Hydrophilic nonacidic side chains O HO COOH Serine (Ser) H2 N H H H H H2 N H2N H2N O OH COOH Threonine (Thr) H2N COOH Asparagine (Asn) H2N COOH Glutamine (Gln) Amino Acids Hydrophilic acidic side chains O HO O HO H H H HO H2 N H2N COOH Aspartic acid (Asp) H2N COOH Glutamic acid (Glu) COOH Tyrosine (Tyr) Hydrophilic basic side chains H N H2N H H2N Lysine (Lys) N HN COOH H H NH2 HN H2 N Arginine (Arg) COOH H2 N COOH Histidine (His) Amino Acids Form Peptides Amino acids link via peptide bond (an amide); form chains Example: OH CH3 H H OH Ala H O Ser OH N N N H H OH H O O Val - H2O CH3 H H Serine rotation? O N OH N H N O H O OH Amino Acids Form Peptides Ala Ser CH3 H H N-terminus Val O N OH N H C-terminus N O H O OH •A tripeptide (three amino acids) •Naming: Val-Ser-Ala or Ala-Ser-Val? N-terminus → C-terminus •Amino acid sequence = primary structure •Like amino acids, peptides and proteins also have zwitterionic forms: CH3 H O CH3 H N O N H2N N O H OH COOH H3N N O CO2 H OH How Does Peptide Bond Influence Structure? O O H N N H Trans Cis Amino acid chain opposite sides C-N bond Amino acid chain same side of C-N bond •Torsional strain: trans < cis; equilibrium favors trans isomer by ~ kcal mol -1 •Amide is conjugated: Conjugation effects: Barrier to rotation around C-N bond ~16 kcal mol -1 O δ− O δ+ N H C C N is planar H The Protein Conformation Problem staggered trans or cis H Consider major conformational isomers of a glycine peptide: O N O staggered Each glycine has x x = 18 major conformations Verify with models A small protein consisting of 14 glycine has 1814 = 3.8 x 1017 major conformations! Number of conformations ↑ significantly if more amino acids, or side chains present Problem: Protein function requires well-organized and restricted structure Solutions: •Local conformational restrictions: cis/trans isomers and planarity •Intramolecular hydrogen bonds Results: •Reduced protein flexibility •Reduced structure randomness 10 Secondary Structure •Structural randomness reduced by intramolecular hydrogen bonds •Causes three basic motifs: the secondary structures of proteins α-Helix H H N H •Clockwise spiral down R N O R •H-bonds parallel to axis H O H •Side chains point out from center N H R •Elastic coil: Thinkbook binding O H N R H N O H H H N R O O axis of helix 11 Secondary Structure β-Sheet: Two or more aligned, H-bonded amino acid chains R O H H O R N N-terminus O H H O N H O O R H N N N O R H O R H O R H O H R O H R O H R O H N N N N R H N N C-terminus R O O H H O N N R O H H O N-terminus N R O H H O R C-terminus O H •Parallel (N-termini same end) or antiparallel (N-termini opposite ends) R R R R R R R R R R •The illustrated β-sheet is antiparallel • β-Sheet more rigid/less elastic than α-helix •Significant component of keratin (hair, wool) and silk •Make your own silk: Thinkbook page 100 R R R R R R R R R R R R 12 Secondary Structure (Random) Coil: not really random, just hard to describe 13 Tertiary Structure •Tertiary structure: aspects of protein structure determined by side chain composition Response to environment: side chain orientation depends on environment Polar environment (water) Nonpolar environment (core of cell membrane) Hydrophilic side chains point out point in Hydrophobic side chains point in point out Disulfide bridges: form loop within one chain, or bond two separate chains Cys S S H H S S Cys Found in: •Insulin (3) •Keratin (hair) •Others 14 Quaternary Structure Quaternary structure: association of two or more subunits by noncovalent bonds •Subunits = polypeptides, carbohydrates, coenzymes, etc •Large surface areas → noncovalent forces can be significant magnitude 15 Protein Structure Representations Myoglobin •stores O2 in muscle tissue via heme •~70% α-helix •a globular protein (~spherical shape) Helix = fuchsia Sheet = yellow Coil = white 16 Protein Structure Representations Retinol Binding Protein •Important for vision Helix = fuchsia Sheet = yellow Coil = white 17 Protein Structure Representations Lactate Dehydrogenase •Released in bloodstream by damaged muscles •Indicative of heart damage or failure •Quaternary structure = four identical units •Subject of Chem 153L experiments Helix = fuchsia Sheet = yellow Coil = white 18