Section 1: Chemistry of Life Flashcards
When was the universe born
Believed to be born 14 billion years ago at the time of the ‘big bang’
Predominant elements in the primordial universe
Hydrogen and helium - the smallest elements
Condensed tgt to form first generation of stars
How were C, N and O formed
By fusion of hydrogen and helium under heat and pressure in the stars
Supernovas
Some of the largest stars became unstable and exploded as supernovas
Dispersed all the elements throughout the universe
What elements are humans primarily made of
C, H, O, N
Known as first-tier elements (abundance)
Have strongest tendency to form strong, covalent bonds
Oxygen and hydrogen in living systems
Abundant
Explained by presence of water (H2O) everywhere on the planet and within biological systems
Carbon
Has an electronic structure that can form up to four very strong and stable bonds with other atoms
Can form single, double and triple bonds, each with diff electronic structures and geometries
Provides versatility, scaffolding and diversity in chemical molecules
Second-tier elements
Essential components of biological molecules
Phosphorous and sulfur - forms covalent bonds
Cl, Na, Mg, K, Ca - ionic elements, critical roles in diverse processes
Third and fourth-tier elements
Found in trace amounts, but still have critical roles
e.g. transition metals in centre of period table - structural and catalytic elements
Signs of life =
Evidence of water or ice
Life on our planet is dependent on ______
Water
Primordial earth - water
Cooling and condensation of water provided an aqueous environment within which molecules could form
Primordial earth - reducing atmosphere
Lack of gaseous oxygen
Supports bond formation
Miller Urey experiment
Reproduced primordial “soup” of earth ~4 million years ago
More than 20 amino acids produced, including some not seen in nature
Types of biopolymers
DNA - made from nucleotides
Proteins - made from amino acids
Carbohydrates - made from sugars
What are biopolymers made of
Simple polymers of smaller organic chemical subunits
How are biopolymers formed
Formed from same reaction path of nucleophilic attack coupled with elimination of water for each biopolymer
Why does our body need weak bonds?
Signalling molecules need to be turned on and off, so must bind strongly enough for it to change shape, but must still be able to come off
Electronegativity
A measure of the tendency of an atom to attract a shared pair of electrons (or electron density)
A difference in electronegativity between 2 atoms in a covalent bonding arrangement results in a bond that is polarised
Polarised bonds
Electrons in the bond aren’t shared evenly between the two atoms, and instead are more closely associated with the more electronegative atom
Drawing dipole moments
Arrow from high electron density atom to low electron density atom
Charge-charge interactions
Dependence of energy on distance: 1/r (strongest)
Between atoms that have full positive and full negative charges
Charge-dipole interactions
Dependence of energy on distance: 1/r^2
Related by interparticle distance, so much weaker than charge-charge interactions
Forms a polar molecule with a dipole moment
Between a full positive charge and a partial negative charge (or vice versa)
Dipole-dipole interactions
Dependence of energy on distance: 1/r^3
Between atoms with a partial positive and partial negative charge
Non-polar molecules - charge
Has neither a net charge nor a permanent dipole moment
But when they are close to charged groups, there is a redistribution of e-; called an induced dipole
Charge-induced dipole interactions
Dependence of energy on distance: 1/r^4
Involves inducing a dipole in one non-polar molecule by putting it in close proximity to a full positive/negative atom
Dipole-induced dipole interactions
Dependence of energy on distance: 1/r^5
Between a dipole and an induced dipole
Van der Waals (dispersion forces)
Dependence of energy on distance: 1/r^6 (weakest)
Numerous
Between paired non-polar molecules
Only becomes significant when atoms approach each other very closely
Distribution of e- within a molecule is always fluctuating, so when two non-polar molecules approach closely, the fluctuations tend to localise in an area of +ve charge on one molecule next to a region of partial -ve charge on the second molecule
Aromatic rings - stacking
Fairly strong interaction, made of van der Waals interactions
Rings interact through their pi-orbitals above and below the ring surfaces, where e- are loosely held
Gives rise to mutually attractive induced dipoles
Van der Waals - biopolymers
Though weak in energy, the great numbers of interactions produce a very large stabilising force
e.g. base-pair stacking of DNA, where aromatic bases in DNA stack directly on top of each other as the helix winds around
Base pairs - distance
3.4 Å
The closest distance 2 Cs can make with each other
Hydrogen bonds
Between two electronegative atoms - one ‘donates’ a H to the bond
Between a partial positive charge on the H (donor) and a partial -ve charge on the electronegative acceptor atom
N-H-O-C
Bond length is fixed - rigid
Hydrogen bonds - unique features
Directionality (optimal angle 180 degrees, 90 degrees is possible but v weak)
Partial covalent bond character
Hydrogen bonds - function
Determines structure and properties of biopolymers
Predominant feature of base pairing in DNA - holds molecules tgt and provides means of DNA replication
Non-polar covalent bond
Bonding e- shared equally between two atoms
No charges on atoms
Polar covalent bond
Bonding e- shared unequally between two atoms
Partial charges on atoms
One atom has a stronger tendency to pull e- towards it than the other
Ionic bond
Complete transfer of one or more valence e-
Full charges on resulting ions
Intramolecular and intermolecular forces
Dominated by weak, non-covalent interactions
Hydrogen bonds - O lone pairs
If lone pairs are directed towards H, then the bond is very strong
Hydrogen bonds - distance from O to H
Sum H + O vdW radii: 2.6 Å (the closest we would expect a H and O to approach each other
Actual H-O distance: 1.9 Å
Discrepancy: 0.7 Å
Due to element of e- being shared and partial covalent behaviour
nm to Å
1 nm = 10 Å
Unique properties of water
Hydrogen bonding ability
Polar nature
Water - hydrogen bonding ability
Can form 4 H bonds with other molecules, particularly other water molecules by its 2 H atoms and 2 sets of lone pairs of e-
Provides water with a high bpt and heat of vapourisation
Predominant state of water
Liquid
Similar sized molecules are gaseous molecules
Water - heat capacity
Very high
Affords a nearly constant temp in large bodies of water
In essence, acts as a temperature buffer
Water is the _______ of life
Universal solvent
Allows molecules to move around and interact in a common medium
Water - ionic compounds
Cations and anions dissociate from their salt crystal and become hydrated by ‘shells’ of water molecules
Polarity of water molecule allows them to surround and coordinate +vely and -vely charged species and shields them from re-associating into an ionic crystal
Water and hydrophilic molecules / functional groups
Dissolve readily because of their charge / polarity in the highly polar water solvent
Forms H bonds to water molecules
Water and hydrophobic molecules
Non-polar, non-ionic and can’t form H bonds –> limited solubility in water
When they do dissolve, they don’t attract hydration shells, and instead water cages / clathrate structures form around the hydrophobic molecule
Water and amphipathic molecules
Produces monolayers, micelles, bilayers, and vesicles
Ka
Acid dissociation constant
pKa
Describes the propensity of a functional group (any weak acid) to dissociate at a specific pH (often pH ~7)
pH and pKa
If pH < pKa, functional group will most likely be in acid form (protonated)
If pH > pKa, functional group will most likely be in base form (deprotonated)
If pH = pKa, side chain has an equal probability of being in the protonated or deprotonated form
pH in human body
Varies between 2 and 8
Often very tightly controlled by buffering systems
Buffer system
Resists changes in pH when an acid or base is added
Systems maintaining pH in human blood
Renal system
Respiratory system
Chemical buffering system
All interplay to keep blood pH tightly regulated
Chemical buffers in blood
Bicarbonate (dominant)
Phosphate
Protein
Dissolution of CO2 in water
Catalysed by enzyme carbonic anhydrase
Produces carbonic acid (weak acid) –> dissociates to produce bicarbonate (conjugate base) and H+
CO2 in water - equilibrium
Addition of acid or base, or changes in bicarbonate (renal system) or carbon dioxide (respiratory system) conc in blood, pertubates the chemical equilibrium
Equilibrium shifts so pH is maintained in range 7.35-7.45
pH of blood at lungs
Tends towards a higher pH (less acidic) than at the tissues that are more acidic
Promotes release of oxygen at the tissues
Assembly of higher order structures of α-keratin
- Monomer - composed of an α-helical domain (amphipathic) and a globular domain. Every 4 amino acids is hydrophobic.
- Dimer (made of 2 monomers) - coiled-coil. Hydrophobic effect (hydrophobic regions inside coil) and vdW interactions
- Protofilament (made of 2 dimers) - join tgt by various weak interactions
- Protofibril (made of 2 protofilament) - join tgt by various weak interactions
α-keratin and water
Water molecules can get in between the protofibrils, which disrupts weak interactions causing it to slide freely
Once dry again, it is set in place of where the interactions were
α-keratin - disulphide bonds
2 cysteine -SH chains = -S-S- bond
Can use a reducing agent to break the disulphide bond back into their -SH groups
α-keratin and hair
More disulphide bonds between cysteines = stronger and curlier hair
Burnt hair smells sulfurous
Perms use a reducing agent to break disulphide bonds, which are then rearranged and neutralised –> stays in place
What is required to change the state of water
To make water into ice or vapour requires energy, because the default state of H2O on this planet is liquid
pKa and Ka equations
pKa = -log10 (Ka)
Ka = { [A-][H+] } / [HA]Adding strong acid or base into a buffer system
Protons combine with conjugate base to produce more weak acid
Strong base takes proton from weak acid to produce more weak acid
CO2 pathway - bicarbonate system
CO2 –> CO2 + H2O –eq arrow– H2CO3 –eq arrow– HCO3- + H+
Production of H+ causes pH to drop, therefore blood pH changes during exercise
Interplay between buffer, respiratory and renal systems
During exercise, cell metabolism increases and produces more CO2 –>
More CO2 dissolves in blood, forming carbonic acid which lowers blood pH slightly –>
Receptors in brain sense the drop in pH and send nerve signals to increase breathing rate –>
Increased breathing rate quickly moves more CO2 from blood. Blood pH rises slightly, returning to normal –>
Homeostasis CO2 level in body
Prion proteins
Mis-shapen / disease forms of ‘normal’ brain proteins
Can interact with normal versions of same protein and convert them in a chain reaction –> forms amyloid fibres (toxic)
Appear to be infectious
Very stable - can’t boil, radiate etc
Normal form: α-helix, disease form: β-pleated sheet –> assembled into long structures
Proteins - folding
Amino acid sequence of proteins contain all the info required for it to spontaneously fold up
High cooperative and happens very quickly
For spontaneous folding…
Gibbs Free Energy must be negative
Energy of folded protein will be lower than that of the unfolded protein
Overall small decrease in energy
Folding proteins - cost
Folding up a protein costs energy
Energy cost doesn’t favour spontaneous protein folding
But there are also gains made back to lower the overall energy of the system
Folding proteins - gains
1: Formation of intramolecular non-covalent interactions; salt bridges (charge-charge), H bonding, and vdW interactions add up to a large energy stabilisation overall
Lowering of energy –> -ve value in ΔH
2: Hydrophobic effect; entropy of water system surrounding the protein. As protein folds up, hydrophobic side chains cluster tightly tgt in interior of protein and form vdW interactions
Hydrophilic side chains can form H bonds with water - water molecules themselves aren’t forming cage structures but have full H bonding freedom
System higher in entropy –> more subtracted from equation –> more negative change in energy overall
Energy difference between folded and unfolded proteins
Small
Only just stable and can be easily unfolded - if too stable, can’t be broken down easily by cell
Inherently (or intrinsically) unstructured proteins
No defined structure until they interact with other molecules - then they fold into specific 3D shapes
A single protein of undefined structure can bind to multiple binding partners and potentially in multiple conformations
Metamorphic proteins
Exist as an ensemble of structures that have equal energies and are in equilibrium with each other
Amyloid disease
Specific proteins can partially unfold or completely change structure (unfold and refold), resulting in inappropriate β-sheet assemblies that deposit/associate in the body as aggregates or fibrils
Energy landscape for diseases - fibril structures
Low energy species
Drive progression of disease
Change from ‘normal’ protein to disease form involves a switch from intramolecular to intermolecular interactions, resulting lowering in free energy
Alzhiemer’s disease
Lots of holes in brain
Hard to diagnose as you can’t take out brain tissue, so must look at symptoms
Possible ways to end up with sporingforms disease
Eating tissue infected with PrP-res
Inherited mutation in gene that codes for PrP-res
PrP-res forms spontaneously
Protein sequence - variables
Length
Amino acid sequence
Protein folding - equilibrium
Most proteins are folded up at equilibrium
Water and ice density
Ice less dense than water, otherwise planet would be covered in ice
Frozen hydrocarbon more dense than liquid
Astrocytes
Cells that crawl through the brain digesting the dead neurons –> leaves holes in the brain
Amyloid fibres remain in brain
Examples of stable proteins
GFP - from jellyfish, barrel structure
Antibodies - exquisite specificity for any one of 100 million antigens
Most proteins are only just stable
Antibodies (immunoglobulin) - function
Bind to foreign molecules (antigens) and neutralise them
Body can produce > 100 million diff antibodies against diff antigens
Must bind with high affinity and selectively
Domains
Separately folded regions of the same protein
Why?
- Efficient folding - longer chains in domain of 100-300 amino acids
- Active sites created in clefts between domains
- Diff activities combined
- Allows flexibility - important for function, e.g. domains close over bound substrate
Quaternary and oligomeric structure
Several separate polypeptide chains cluster tgt
Oligomer = many units (monomer, dimer, trimer, tetramer etc)
IgG antibodies (immunoglobulin G)
Multi-domain and multi-chain proteins Y-shaped molecule Tetramer: - 2 heavy chains folded into 4 domains each - 2 light chains folded into 2 domains each Flexible hinges between domains Very stable Disulphide bonds present
IgG antibodies - loops
Each variable domain has 3 hypervariable loops –> 6 at each site –> 12 per antibody
Loops which have diff sequences depending on which antigen they bind to
IgG antibodies - flexibility
Flexible linkers
Y-shaped arms can open and close
Allows a single antibody to bind 2 antigens at the same time with adjustable distance –> strongest binding to a foreign body
How does antibody recognise antigen
Molecular recognition by: Shape Size Charge Polar/non-polar character
Blood sugar levels
Varies throughout the way
How is blood sugar regulated
Pancreas secretes insulin and glucagon
If blood sugar high, insulin helps cells absorb glucose –> reduces blood sugar and provides glucose for energy
If blood sugar low, glucagon instructs liver to release stored glucose –> raises blood sugar
Glucagon shape
α-helix
Glucagon receptor mainly recognises…
Shape
Size/length
Weak interactions (chemically), most of which found in side chains of protein
Glucagon - examples of pockets
Non-polar surrounded by non-polar Opposite charges attracting H-bonds forming (if bond is short) Site 18 (ARG) causes pi-stacking - a special case of charge-induced dipole
Oxyanion site
Where 2 Hs with +ve charges balance out the very -ve O
In glucagon receptor, NOT an oxyanion site, but in an enzyme might be
Zoonotic diseases in human populations - pathway
- Virus emerges
- Animal reservoir (Primary host)
- longevity
- low virulence
- asymptomatic - Intermediate host
- Human disease
- transmission to humans
- mutation and adaptation to humans
- transmission between humans (may have decreased virulence, but easier to spread) - Dissemination
Cytokine storm
Highly virulent strains of viruses that kill healthy young individuals through an overreaction of the immune system
What two surface proteins are required for entry and exit of virus from our cells
Hemagglutinin
Neuraminidase (aka sialidase)
Both recognise sialic acid molecules on glycosylated receptor proteins
Why is it difficult for humans to directly catch influenza strains from wild birds
Because the way sialic acid is ‘presented’ on the host cell surface (i.e. its shape) in bird and human receptors are different
16 types of HA: H1-16
9 types of NA: N1-9
Only 3 types have adapted to infect humans so far; H1N1, H2N2 and H3N2
Life cycle of influenza virus - 2 steps
- Hemagglutinin molecular recognition of sialic acid
2. Neuraminidase molecular recognition of sialic acid and cleaves it away from receptor
Sialic acid linkage - birds vs humans
Human: α-2,6 linkage
Bird: α-2,3 linkage (straight line)
Pigs, birds and humans - catching and spreading viruses
Humans have α-2,6 receptors near mouth (closer to outside) and α-2,3 receptors in lungs (harder to reach)
Birds only have α-2,3 receptors, so less likely to reach humans
Pigs have both α-2,3 and α2,6 outside, so can catch the virus from both humans and birds, and can give the virus to humans as well
Enzyme active sites are meant to…
Stabilise transition states
Intermediate hosts - mechanisms/causes
Land use / encroachment Domestication Farming practices Trade/travel Consumption / bush meat Climate Pop changes
Sialic acid ring
In initial binding event, it changes conformation from chair to boat
Boat conformer is higher energy –> promotes catalysis through a higher energy transition state
α-helices
Usually right-handed
How are α-helices and β-sheets defined
By their backbone H-bonding
Globular proteins
Driven to fold by hydrophobic effect
Sialic acid recognised by hemagglutinin
Located at the top of a carbohydrate chain attached to a host cell membrane protein
