lecture 3 - from chemistry to biology

Lecture 3 From Chemistry to Biology:

Using Energy to Create Order and Complexity

Prof. John Bellizzi August 28, 2015

Chemistry 3510 BIOCHEMISTRY I

From Chemistry to Biology •  Biogenesis (formation of building blocks) •  Association to form simple self-‐‑replicating

molecules •  Primitive cells •  Evolution by natural selection Primordial Earth’s atmosphere •  very liIle O2 •  mostly H2O, N2, CO2 (like today), plus CH4,

NH3, H2, SO2 (all molecules found in interstellar space)

•  reducing environment, not oxidizing environment.

UV radiation, lightning led to the formation of water-‐‑soluble organic molecules from these precursors (including nucleotides, amino acids) Thin “primordial soup” may have become concentrated in tide pools, shallow lakes to allow monomers to condense and form peptides, oligonucleotides). Miller-‐‑Urey experiment (1953).

Lecture 3 8/28/15 Biochemistry I Prof. Bellizzi 2

RNA World Hypothesis

Modern biochemistry: •  DNA = information storage (no catalytic

function) •  Protein = catalytic function (no information

storage) •  RNA is the intermediate connecting the two However, some RNA molecules can catalyze reactions as well as carry information. Life may have begun as self-‐‑replicating catalytic RNA molecules, which over time became templates for protein synthesis. DNA is more stable than RNA, so the adaptation to store sequences as DNA rather than RNA would have beIer preserved the information content.


Equilibrium

•  Many chemical reactions (and physical processes) are reversible.

•  When a reaction is at equilibrium, the rate of the forward reaction is exactly the same as the rate of the reverse reaction.

•  At equilibrium, there is no net change in the concentrations of reactants and products.

•  All closed thermodynamic systems (no exchange of energy/maIer with surroundings) will eventually reach equilibrium.


Thermodynamics

•  Tells us whether a given reaction or process can occur spontaneously

(thermodynamically favorable), or whether it needs an input of energy to drive the reaction (thermodynamically unfavorable).

•  Independent of the path from start to finish – only the energies of the starting materials and products

•  Says nothing about the rate of the reaction/process.

•  Living organisms are open thermodynamic systems (exchange energy and maIer with surroundings)!


Spontaneity and Equilibrium

A process is spontaneous (thermodynamically favorable) if it will move the system towards equilibrium.

•  Keq = 1: system at equilibrium •  Keq >1: forward reaction moves system towards equilibrium (Forward reaction

spontaneous) •  Keq <1: reverse reaction moves system towards equilibrium (Forward reaction

not spontaneous) Standard Gibbs Free Energy: ΔG° = -‐‑RT ln Keq

•  Keq = 1 ΔG° = 0 (system at equilibrium) •  Keq >1 ΔG° < 0 (spontaneous) •  Keq <1 ΔG° > 0 (not spontaneous)

ΔG° represents “standard conditions”: 25 °C, 1 M concentrations. ΔG under arbitrary concentrations is a function of ΔG° , T and starting concentrations


ΔG = ΔGo +RT ln[C]ic[D]i

d

[A]ia[B]i

b

Thermodynamic State Functions

Gibbs Free Energy: ΔG = ΔH – TΔS Enthalpy (Heat and Work): H

•  1st Law: Energy cannot be created or destroyed •  Related to the number and kinds of bonds •  ΔH reflects kinds and numbers of bonds and noncovalent interactions

formed/broken •  ΔH < 0 if heat is released (exothermic)

Entropy (Randomness, disorder): S •  2nd Law: For a spontaneous process, ΔSuniverse > 0 •  If local entropy decreases, this must be offset be a greater increase of

entropy in the surroundings •  ΔS > 0 if randomness/disorder increases

A spontaneous process (thermodynamically favorable process) has ΔG < 0 •  Free energy is released •  Free energy of products is less than that of starting materials •  Exergonic reaction

Note that a thermodynamically favored process may be kinetically very slow (more on this later). Lecture 3 8/28/15 Biochemistry I Prof. Bellizzi 7

Dynamic Steady State

•  Once mature, organism maintains a more or less constant composition (steady state)

•  Are organisms at equilibrium? •  Systems at equilibrium cannot do work •  Living organism is different in chemical

composition from surroundings •  If you ever reach equilibrium, it means you’re

dead!

•  Living things are steady-‐‑state systems, but it is a dynamic steady state

•  There is a huge flux of energy and maIer through a living system (metabolism).

•  This energy is required to keep us from reaching equilibrium and to maintain a great deal of biochemical information (which costs energy….).


We ingest high enthalpy, low entropy nutrients and convert them to low enthalpy, high entropy waste products. Glucose oxidation: C6H12O6 + 6 O2 → 6CO2 + 6 H2O ΔH° = -‐‑2808 kJ/mol ΔH°< 0 ΔS° > 0 ΔG° < 0 Thermodynamically favorable (spontaneous)


Energy Coupling

Reactions that are thermodynamically unfavorable…. •  Synthesis of high enthalpy, low entropy

molecules •  Chemical, physical work … can be driven by coupling them to spontaneous reactions! Rxn 1 – unfavorable (ΔG > 0) Rxn 2 = favorable (ΔG < 0) Couple the two reactions together (add ΔGs) Net negative ΔG!


ΔG° kJ/mol

Adenosine Triphosphate (ATP)

ATP is the universal energy currency of life •  Energy (from oxidation of organic compounds or photosynthesis) is used to

synthesize ATP •  The accumulated ATP can then be “spent” to drive endergonic reactions. Hydrolysis of phosphoanhydride bonds (ATP+H2O→ ADP+Pi) or (ATP+H2O→ AMP+PPi) Is highly exergonic Reasons: •  Reduce charge-‐‑charge repulsion •  Resonance stabilization •  [ATP] maintained much higher than equilibrium concentration


Thermodynamic stability vs. kinetic stability Biological macromolecules are thermodynamically unstable compared to their monomer subunits (energy has to be input to synthesize them). Sugar is very unstable relative to CO2 and H2O, but it does not spontaneously combust! Thermodynamically unstable, but kinetically stable. The rate of reaction is immeasurably slow. In a cell, there are many compounds that are thermodynamically unstable but kinetically stable, and therefore many potential spontaneous reactions. What determines which reactions actually occur, and when and where?


Enzymes

Enzymes (biological catalysts) •  Like all catalysts

•  accelerate reactions by lowering activation barrier (ΔG‡) •  do not alter ΔG° (position of equilibrium unchanged)

•  Routinely accelerate rates by 1012

•  High specificity •  Ability to be precisely regulated •  Almost always proteins

•  Sometimes with coenzymes •  Occasionally RNA

Of all the possible reactions that are thermodynamically favorable in a cell, the ones that occur on a reasonable timescale are generally the ones that are enzyme-‐‑catalyzed.

Enzymes also are critical for coupling exergonic reactions with endergonic reactions.


Biochemical Information

Biomolecules are large and complex in structure and have a diverse array of functions. These structures and functions are not random – they contain information. •  The structure and biological function of a protein (e.g. an enzyme or receptor) is

dependent on the sequence of amino acids in the polypeptide chain (a string of information).

•  That sequence of amino acids is specified by the sequence of nucleotides in the DNA that makes up the gene encoding that protein.

Life depends on the ability of these information-‐‑containing molecules to faithfully store and transmit this information (Genetics). Chemical and physical processes can alter the information content. In rare cases, this leads to individual organisms beIer adapted to survive (Evolution by natural selection). Information and complexity are related to entropy! They make a significant contribution to ΔG and can be considered a form of energy!


Genetic Information DNA is the cell’s repository of genetic information. Information = sequence of bases (A, C, T, G) in a single strand of DNA. The molecular structure of DNA allows the information encoded in the sequence of bases to be replicated faithfully. •  Specific hydrogen bonding interactions create base

pairs between A:T and C:G on different strands •  Two strands with complementary sequences form a

double helix. •  When a cell divides, one strand of DNA can serve

as the template for synthesis of a new strand of complementary DNA (DNA replication)

•  A strand of DNA can also serve as the template for synthesis of an RNA molecule with a complementary sequence (DNA transcription).

•  The complementary nature of the two strands provides a “backup copy” allowing for repair if one of the two strands is damaged.


The Central Dogma of Molecular Biology

DNA→ RNA→ Protein Sequence of deoxyribonucleotides in DNA encodes sequence of amino acids in protein. Different proteins have different sequences of amino acids, different three-‐‑dimensional structures, different functions. •  Gene = coding sequence for a

protein •  Coding sequence is transcribed into

mRNA. •  Ribosomes translate mRNA to

protein (unfolded polypeptide chain)

•  Sequence of amino acids in protein lead to the protein folding into a particular native three-‐‑dimensional structure.


Comparative Genomics

Genome – complete sequence of genetic material of an organism. Homologs – two genes/proteins with similar sequence

•  nucleotide sequence in DNA or amino acid sequence in encoded protein •  Proteins encoded by homologous genes have same 3D structure and same/

closely related function •  The greater the sequence similarity, the closer the structure and function

Orthologs – homologous genes/proteins found in two different species

Example: human hexokinase and yeast hexokinase Paralogs – homologous genes/proteins found in same species

Example: human myoglobin and human hemoglobin A. Similarities/differences in DNA sequences among organisms indicates descent from common evolutionary ancestor, allows us to determine their relationship.


Evolution Enormous variety of life-‐‑forms on earth is the product of billions of years of evolution. •  Chance genetic variations in population (mutation) •  Leads to individuals with improved fitness in environmental niche (natural selection) Change in nucleotide sequence = genetic mutation Can be caused by physical/chemical damage to a DNA molecule or by (very rare) unrepaired error in DNA replication. Mutations in somatic cells can lead to cell death or cancer Mutations in germ cells (sperm or egg) can be passed on to new organism •  Most mutations are harmful or lethal (lead to defect in a particular protein) •  Rarely, a mutation causes a change in the structure or function of a protein that is tolerated

by the new organism/cell •  In a subset of those cases, the mutation beIer equips the offspring to survive in its

environment. Example: •  Mutation in a gene encoding an enzyme that changes the enzyme’s substrate specificity. •  The mutant offspring may be able to metabolize a compound that the wild-‐‑type cell/

organism cannot. •  If that compound is abundant in the environment, the mutant offspring has a source of

energy/carbon that the wild type cell/organisms does not.


Gene Duplication

Many mutations have arisen after a gene duplication event. Defective replication can sometimes lead to duplication of large stretches of DNA, including entire genes. This can allow one copy of the gene to mutate without compromising the activity of the encoded protein (because the other copy of the gene still supplies the code for that protein).


lecture 3 - from chemistry to biology

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