Module 2

Noncovalent Bonds

Weak and short-term intermolecular interactions

Noncovalent: Electrostatic Interactions

Ionic/salt bridges
Positive and negative charges form bonds

Noncovalent: Molecular Dipoles

Slightly positive and negative charges
Dipoles align to maximize electrostatic interactions

Noncovalent: Hydrogen Bonds

Determine structure and function of molecules

Hydrogen Bond: H Donor

EN atom
Partial positive H bonded to EN atom
Strong dipole moment

Hydrogen Bond: H Acceptor

Atom with lone pair
Partial positive H interact with lone pair
Strong electrostatic interaction

Noncovalent: Amphipathic Molecules

Produce hydrophobic effect
Phospholipids:
Polar heads associate with water
Nonpolar tails avoid water

Noncovalent: Hydrophilic Molecules

Readily dissolve in water
Ionic and polar

Noncovalent: Hydrophobic Molecules

Not readily dissolve in water
Nonpolar

Amino Acid

Organic molecule with 4 groups bound to alpha-carbon

Amino Acid Structure: A-Amino Group

1-3 H
Depend on pH and N

Amino Acid Structure: A-Carboxyl Group

Lose H from OH = negative charge

Amino Acid Structure: Side Chain R Group

Classify amino acid
Affect behaviour

Nonpolar R Group

No proton gain/loss
No H/ionic bonds
Hydrophobic
In protein core or interacting with phospholipid tails
9 amino acids
(I Glided Low and Tripped Mr. Alan Phenyl Very Profanely)

Glycine

Gly
G
Nonpolar
Smallest side chain
Flexible

Alanine

Ala
A
Nonpolar

Valine

Val
V
Nonpolar

Leucine

Leu
L
Nonpolar

Isoleucine

Ile
I
Nonpolar

Phenylalanine

Phe
F
Nonpolar
Aromatic

Tryptophan

Trp
W
Nonpolar
Aromatic

Methionine

Met
M
Nonpolar
SCH side chain

Proline

Pro
P
Nonpolar
R group bound to a-amino
Rigid ring
Kinks in protein

Uncharged Polar R Group

H bond
Outside of protein
6 amino acids
(Sarah Thought Tyler Glued Asparagus to Cat)

Serine

Ser
S
Polar
OH form H bonds

Threonine

Thr
T
Polar
OH form H bonds

Tyrosine

Tyr
Y
Polar
Aromatic
OH lose H at alkaline pH

Asparagine

Asn
N
Polar
Carbonyl + amine

Glutamine

Gln
Q
Polar
Carbonyl + amine

Cysteine

Cys
C
Polar
Thiol (SH)
Disulfide bonds
lose H at alkaline pH

Acidic R Group

2 amino acids
(Acids)

Aspartic Acid

Asp
D
Acidic
Negative

Glutamic Acid

Glu
E
Acidic
Negative

Basic R Group

3 amino acids
(Lyzzie Argued Historically)

Histidine

His
H
Basic
Positive

Lysine

Lys
K
Basic
Positive

Arginine

Arg
R
Basic
Positive

Aromatic R Groups

Large
Cause steric hindrance
Gain/loss cause protein deformities
3 amino acids
(Phoenix Tripped Tiger)

Chirality

Non-superimposable mirror images
Enzymes interact with 1 chiral substrate
Chiral centre attached to 4 different groups

Free Amino Acids

Amino acids not in peptide bonds
Carboxyl: weak acid
Amino: weak base
In acid-base reactions

Henderson-Hasselbalch Equation

Relationship between pH and concentration of weak acid and conjugate base

Buffers

Resist pH changes
Model with titration curve
Protonated buffer : Deprotonated buffer

Free Amino Acids with Non-Ionizable Side Chain

2 buffering groups
Carboxylic: pK1 = 2.3
Amino: pK2 = 9.1
Positive to neutral to negative
Carboxylic then amino lose protons

Non-Ionizable Titration Curve

Carboxylic lose proton
Isoelectric point (neutral)
Amino lose proton

Non-Ionizable pH Plot

Fully protonated
Carboxyl lose proton
Zwitterionic form
Amino lose proton
Fully deprotonated

Free Amino Acids with Ionizable Side Chains

3 buffering groups
Carboxylic: pK1
Amino: pK2
R-group: pKR
7 amino acids
(acidic, basic, tyrosine, cysteine)

Buffers in Body

Maintain pH for survival

Body Buffer: Bicarbonate Buffer in Blood

Increase CO2 decreases pH
Respiratory acidosis

Bicarbonate in Blood: pH Decrease

Bicarbonate bind free H+
Form carbonic acid
Release CO2 and H2O

Bicarbonate in Blood: pH Increase

Carbonic acid release H+
Form bicarbonate

Body Buffer: Drug Absorption

Depend on local pH
Uncharged drugs easily absorbed (Non-polar cell membrane)

Drug Absorption: Aspirin in Stomach

Acidic stomach
Aspirin protonated and uncharged
Well absorbed

Drug Absorption: Aspirin in Small Intestine

Aspirin unprotonated and negative
Poorly absorbed

Protein

Linear polymer of amino acids
R-groups and environment determine folding
3D structure determine function

Post-Translational Modifications

Covalent changes affecting protein folding
Assisted by chaperone proteins

PT Mod: Disulfide Bonds

Thiol group in cysteine lose H
Stabilize protein

PT Mod: Glycosylation

Attach carbohydrate
N-Linked: Amide in asparagine
O-Linked: Hydroxyl in serine/threonine

PT Mod: Phosphorylation

Attach phosphate to hydroxyl in serine, threonine, and tyrosine
Alter protein conformation
Turn enzymes on and off

Phosphorylation: Kinase

Enzyme adding phosphate

Phosphorylation: Phosphatase

Enzyme removing phosphate

Primary Protein Structure

Linear amino acid sequence joined by peptide bonds
No R group interactions
N-terminal: left
C-terminal: right

Primary: Peptide Bond

Between carboxyl and amino groups
Stable

Peptide Bond Formation

Condensation reaction
Remove water

Peptide Bond Cleavage

Hydrolysis
Require water and enzymes

Peptide Bond Characteristics

Resonance
Rigid and strong
Planar
Trans conformation

Peptide Bond Conformation

Cis: 2 a-carbons on same side causing steric hinderance
Trans: 2 a-carbons on opposite sides with no steric hinderance

Peptide Bond Polarity

Uncharged polar carbonyl and amino groups
Charged groups:
N-terminal
C-terminal
Ionized side chains

Secondary Protein Structure

Amino acid chain folding
Maximize H bonding

Secondary: Alpha Helix

Most common
Right-handed spiral

Alpha Helix Structure

Backbone core stabilized by H bonds
Between carbonyl O and amide H (parallel)
Outer side chains (perpendicular)
Similar side chains group together

Amphipathic Alpha Helix

Polar and nonpolar face

Alpha Helix Breakers

Bulky and rigid amino acids not fitting in a-helix
Charge clusters disrupt ionic interactions
Proline
Aromatic
Branched (Leucine)

Secondary: Beta Sheet

b-strands connected by H bonds
Parallel or antiparallel
Between carbonyl and amide (perpendicular)

Beta Sheet Structure

Fully extended backbone
Side chains above and below
Similar side chains group together

Secondary: Motifs

Supersecondary structure
Combo of a-helices and b-sheets
Non-functional unit
Secondary structure stabilization
Non-covalent interactions

Tertiary Protein Structure

Domain folding and 3D arrangement
Contain:
a-helices
b-sheets
unfolded primary structures

Tertiary: Domain

Functional 3D structural unit
Independent folding
1+ domain per protein

Tertiary: Conformation

Tight packing in aqueous solution
Hydrophobic amino acids on inside
Hydrophilic amino acids on surface

Tertiary Stabilizing Interactions: Disulphide Bond

Link cysteines

Tertiary Stabilizing Interactions: Hydrophobic Interactions

Association of nonpolar side chains
Protein core

Tertiary Stabilizing Interactions: H Bonds

Between O and N
Between polar groups on protein surface

Tertiary Stabilizing Interactions: Ionic Interactions

Negative and positive side chains interact
Stabilization

Quaternary Protein Structure

2+ protein chains/subunits bind
Stabilized by noncovalent interactions
Linear chains
Globular

Protein Monomer

1 protein unit
No quaternary structure

Protein Folding

Ordered process
Driven by side chain interactions

Protein Folding 1

Primary structure forms secondary structure (a-helices and b-sheets)

Protein Folding 2

Helices and sheets form domains
Hydrophobic effect drives domain folding

Protein Folding 3

Domains combine to form protein monomers
Hydrophobic core drives folding

Protein Folding 4

Monomers bind
Form larger proteins

Protein Folding Diseases

Accumulation of misfolded proteins

Protein Disease: Alzheimer's 1

Abnormal cleavage of amyloid precursor protein
Cleave and release hydrophobic section of neuron

Protein Disease: Alzheimer's 2

Produce beta-amyloid protein
B-sheet structures aggregate in plaques

Protein Disease: Alzheimer's 3

Neurotoxicity
Cell death and cognitive impairment

Protein Disease: Prion Disease

Transmissible spongiform encephalopathies
Creutzfeldt-Jakob disease
Scrapie
Mad cow disease

Protein Disease: Prion Disease 1

Non-infectious a-helices fold into infectious b-sheets

Protein Disease: Prion Disease 2

Misfolded protein form long insoluble fibres
Resist degradation

Proteins in Cellular Functions

Ion and molecule transport
Structural framework
Mediate immune response
Enzyme catalysts

Globular Proteins

Spherical
Hydrophobic core
Hydrophilic exterior
Secondary, tertiary, quaternary structures

Globular Protein Functions

Transporters
Storage
Enzymatic activity
Ex: Hemoglobin

Fibrous Proteins

Long parallel chains of twisted multimers
Stabilize by disulfide bridges