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 Proteins
Lecture Supplement page 238
Why Bother With Protein Structure?
Molecular structure controls function
N
H O
HR
n
Repeating unit
N
H O
N
HR
N
H O
N
HRH
H R
O OH
H R
•Enzyme selectivity•Drug design•Many others
Fundamental protein structure = amide polymer
N
H O
HR
OHH
Amino AcidsThe Fundamental Building Block of Peptides and Proteins
N
O
HR
OH
H H
All amino acids have amine and carboxylic acid groups
•All are primary amines (R-NH2) except proline
Amine (base) + carboxylic acid = proton transfer possible:
Neutral (unionized) form Zwitterionic (ionized) form
Keq > 1 atphysiological pH
-carbon •Side chains (R) vary
•18 are S, 1 is R, 1 is achiral
N
H O
HR
OHH
H2N COOH
HHN
Amino AcidsThe 20 standard amino acids categorized by side chain properties:•Hydrophilic versus hydrophobic
Hydrophobic nonacidic side chains
Glycine (Gly)Achiral
Alanine (Ala) Valine (Val) Leucine (Leu) Isoleucine (Ile)
Proline (Pro)2o amine (HNR2)
Tryptophan (Trp) Phenylalanine (Phe) Methionine (Met)
H2N COOH
HH
•Acidic versus basic versus neither (nonacidic)
H2N COOH
HH3C
H2N COOH
H
H2N COOH
H
H2N COOH
H
COOHN
H
H H2N COOH
H
H2N COOH
H
CH3S
Amino AcidsHydrophobic acidic side chains Side chain more acidic than water
Cysteine (Cys)
Hydrophilic nonacidic side chains
H2N COOH
HHS
H2N COOH
HHO
H2N COOH
H
OH
H2N COOH
H
O
H2N
H2N COOH
H
O
H2N
H2N COOH
HHO
Tyrosine (Tyr)
Serine (Ser) Threonine (Thr) Asparagine (Asp) Glutamine (Gln)
Amino AcidsHydrophilic acidic side chains
Hydrophilic basic side chains Nitrogen lone pairs to accept a proton
H2N COOH
H
O
HO
H2N COOH
H
O
HO
H2N COOH
HH2N
H2N COOH
H
N
H
HN
NH2 H2N COOH
HHN
N
Do 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 chains
N
H O
OHH
CH3
Ala
N
H O
OHH
OH
Ser
N
H O
OHH
Val
N
H O
N
OHH
N
O
CH3
H
H O
OH
Serine side chain configuration?
Verify with model of complete tripeptide
-2 H2O
Amino Acids Form Peptides
•A tripeptide (three amino acids)•Naming: Val-Ser-Ala or Ala-Ser-Val? N-terminus C-terminus
N
H O
N
OHH
N
O
CH3
H
H O
OHN-terminus C-terminus
Ala Ser Val
•Amino acid sequence = primary structure of peptide or protein•Like amino acids, peptides and proteins also have zwitterionic forms:
H2N
O
N
OHH
N COOH
CH3 H O
H3N
O
N
OHH
N CO2
CH3 H O
How Does Peptide Bond Influence Structure?
TransAmino acid chain
opposite sides of C-N bond
CisAmino acid chain
same side of C-N bond
•Torsional strain: Trans < cis; equilibrium favors trans isomer by ~ 2 kcal mol-1
H
N
O
NH
O
Conjugation effects:Barrier to rotation around C-N bond ~16 kcal mol-1
C
H
NC
O
is planar
•Amide is conjugated:
H
N
O -
+
The Protein Conformation Problem
Consider major conformational isomers of a glycine peptide:
•Each glycine has 2 x 3 x 3 = 18 major conformations Verify with models
•A 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 present
Problem: Protein function requires well-organized and restricted structure
Solutions: •Local conformational restrictions: Cis/trans isomers and planarity
•Intramolecular hydrogen bondsResults: •Reduced protein flexibility
•Reduced structure randomness
O
N
H Otrans or cis
3 staggered
3 staggered
Secondary Structure•Structural randomness reduced by intramolecular hydrogen bonds
-Helix
•Clockwise spiral down
•H-bonds parallel to axis
•Side chains point out from center
•Elastic coil: Thinkbook binding
N
ON
N
R
H N
H
H
O
O
N
H
O
N
O
O
H
RH
H
R
H
H
R
H
R
H
axis of helix
•Causes three basic motifs: The secondary structures of proteins
There is an H-bond between C=O and N-H of residue 1 and residue 4 (residue 2 and residue 5) (… etc.)
Secondary Structure
-Sheet: Two or more aligned, H-bonded -strands
•Parallel N-termini same end) or antiparallel N-termini opposite ends)•The illustrated -sheet is antiparallel• -Sheet more rigid/less elastic than -helix•Significant component of keratin (hair, wool) and silk•Make your own silk: Thinkbook Appendix C
N-terminus C-terminus
C-terminus N-terminus
N
HRO
N
H
N
RO
N
H
N
RO
N
H
N
R
O
H
N
R O
N
HO
N
R
N
HO
N
R
N
HO
N
R
HROHROHRO
ORHORHORH
HHHH
O O O OHHH
O O O
R R R R R
RRRRR RRRRR
R
R
R R R R R
-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 positions
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
S H
H S
Cys
Cys
S
S
Found in:•Insulin (3)•Keratin (hair)•Others
•Aspects of protein structure determined by side chain composition
Quaternary StructureQuaternary structure: Association of two or more subunits by noncovalent bonds
•Subunits = proteins, carbohydrates, coenzymes, etc.
•Large surface areas noncovalent forces can be significant magnitude
Quaternary structure = four subunits
Four levels of protein structure• Primary structure: amino acid sequence
• Secondary structure: alpha helix, beta strand / beta sheets
• Tertiary structure: spatial arrangement of amino acid residues and disulfide bonds
• Quaternary structure: spatial arrangement of subunits and nature of their interactions
Insulin – Primary Structure
Insulin – Secondary Structure and Tertiary Structure
To play with an interactive 3D-Model of the insulin monomer: http://www.pdb.org/pdb/101/motm_disscussed_entry.do?id=4ins
-3 alpha helices-1 beta strand
Insulin – Quaternary Structure
Insulin hexamer (inactive form of insulin; long-term storage in the body)
Protein Structure RepresentationsMyoglobin •stores O2 in muscle tissue via heme
•~70% -helix•A globular protein (~spherical shape)
Helix = fuchsiaSheet = yellow
Coil = white
Worldwide Protein Data Bank: http://www.wwpdb.org/
Protein Structure Representations
Retinol Binding ProteinHelix = fuchsiaSheet = yellow
Coil = white
•Important for vision
Protein Structure RepresentationsLactate Dehydrogenase Helix = fuchsia
Sheet = yellowCoil = white
•Quaternary structure = four identical protein subunits•Released in bloodstream by damaged muscles•Indicative of heart damage or failure•Subject of Chem 153L experiments
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