Biomolecules Survey Part 3: Amino Acids, Peptides, and Proteins Lecture Supplement page 238.

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  • Biomolecules Survey Part 3:Amino Acids, Peptides, and ProteinsLecture Supplement page 238

  • Why Bother With Protein Structure?Molecular structure controls function Enzyme selectivityDrug designMany others

    Fundamental protein structure = amide polymer

  • Amino AcidsThe Fundamental Building Block of Peptides and ProteinsAll amino acids have amine and carboxylic acid groupsAll are primary amines (R-NH2) except prolineAmine (base) + carboxylic acid = proton transfer possible:Neutral (unionized) formZwitterionic (ionized) formKeq > 1 atphysiological pHa-carbonSide chains (R) vary18 are S, 1 is R, 1 is achiral

  • Amino AcidsThe 20 standard amino acids categorized by side chain properties:Hydrophilic versus hydrophobic

    Hydrophobic nonacidic side chainsAcidic versus basic versus neither (nonacidic)

    Glycine (Gly)AchiralAlanine (Ala)Valine (Val)Leucine (Leu)Isoleucine (Ile)

    Proline (Pro)2o amine (HNR2)Tryptophan (Trp)Phenylalanine (Phe)Methionine (Met)

  • Amino AcidsHydrophobic acidic side chains Side chain more acidic than waterCysteine (Cys)Hydrophilic nonacidic side chainsTyrosine (Tyr)Serine (Ser)Threonine (Thr)Asparagine (Asp)Glutamine (Gln)

  • Amino AcidsHydrophilic acidic side chainsHydrophilic basic side chains Nitrogen lone pairs to accept a protonDo I have to memorize amino acid structures?Aspartic acid (Asp)Glutamic acid (Glu)Lysine (Lys)Arginine (Arg)Histidine (His)

  • Amino Acids Form PeptidesAmino acids link via peptide bond (an amide); form chainsSerine side chain configuration?Verify with model of complete tripeptide-2 H2O

  • Amino Acids Form PeptidesA tripeptide (three amino acids)Naming: Val-Ser-Ala or Ala-Ser-Val? N-terminus C-terminusN-terminusC-terminusAlaSerValAmino acid sequence = primary structure of peptide or proteinLike amino acids, peptides and proteins also have zwitterionic forms:

  • How Does Peptide Bond Influence Structure?TransAmino acid chainopposite sides of C-N bondCisAmino acid chainsame side of C-N bondTorsional strain: Trans < cis; equilibrium favors trans isomer by ~ 2 kcal mol-1Conjugation effects:Barrier to rotation around C-N bond ~16 kcal mol-1Amide is conjugated:

  • The Protein Conformation ProblemConsider major conformational isomers of a glycine peptide:Each glycine has 2 x 3 x 3 = 18 major conformations Verify with modelsA small protein consisting of 14 glycine has 1814 = 3.7 x 1017 major conformations!Number of conformations significantly if more amino acids, or side chains presentProblem:Protein function requires well-organized and restricted structureSolutions:Local conformational restrictions: Cis/trans isomers and planarityIntramolecular hydrogen bondsResults:Reduced protein flexibilityReduced structure randomness

  • Secondary StructureStructural randomness reduced by intramolecular hydrogen bondsa-HelixClockwise spiral downH-bonds parallel to axisSide chains point out from centerElastic coil: Thinkbook bindingCauses three basic motifs: The secondary structures of proteinsThere is an H-bond between C=O and N-H of residue 1 and residue 4 (residue 2 and residue 5) ( etc.)

  • Secondary Structureb-Sheet: Two or more aligned, H-bonded b-strandsParallel (N-termini same end) or antiparallel (N-termini opposite ends)The illustrated b-sheet is antiparallel b-Sheet more rigid/less elastic than a-helixSignificant component of keratin (hair, wool) and silkMake your own silk: Thinkbook Appendix CN-terminusC-terminusC-terminusN-terminusb-Strand: A fully extended polypeptide chain (as opposed to being in a helix)

  • Secondary Structure(Random) Coil: Not really random, just hard to describe Key point: Random coils do not have catalytic activity Denatured proteins adopt the shape of a random coil

  • Tertiary StructureTertiary structure: Three-dimensional atomic positionsResponse to environment: Side chain orientation depends on environmentDisulfide bridges: Form loop within one chain, or bond two separate chainsFound in:Insulin (3)Keratin (hair)OthersAspects of protein structure determined by side chain composition

    Polar environment(water)Nonpolar environment(core of cell membrane)Hydrophilic side chainspoint outpoint inHydrophobic side chainspoint inpoint out

  • Quaternary StructureQuaternary structure: Association of two or more subunits by noncovalent bondsSubunits = proteins, carbohydrates, coenzymes, etc.Large surface areas noncovalent forces can be significant magnitudeQuaternary structure = four subunits

  • Four levels of protein structurePrimary structure: amino acid sequenceSecondary structure: alpha helix, beta strand / beta sheetsTertiary structure: spatial arrangement of amino acid residues and disulfide bondsQuaternary structure: spatial arrangement of subunits and nature of their interactions

  • Insulin Primary Structure

  • Insulin Secondary Structure and Tertiary StructureTo play with an interactive 3D-Model of the insulin monomer: alpha helices1 beta strand

  • Insulin Quaternary StructureInsulin hexamer (inactive form of insulin; long-term storage in the body)

  • Protein Structure RepresentationsMyoglobinstores O2 in muscle tissue via heme~70% a-helixA globular protein (~spherical shape)Worldwide Protein Data Bank:

  • Protein Structure RepresentationsRetinol Binding ProteinImportant for vision

  • Protein Structure RepresentationsLactate DehydrogenaseQuaternary structure = four identical protein subunitsReleased in bloodstream by damaged musclesIndicative of heart damage or failureSubject of Chem 153L experiments**


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