Foundations of BioChemistry

The molecular logic of life refers to the underlying principles and organizing concepts that are common to all living organisms at the molecular level.

Biochemistry relates to this by:

• Describing the structures, mechanisms, and chemical processes shared by all organisms
• Revealing how complex properties of life emerge from interactions of simpler molecules
• Demonstrating that living processes follow the same physical and chemical laws as inanimate matter
• Explaining how collections of lifeless molecules interact to maintain and perpetuate life
• Providing organizing principles that underlie life in all its diverse forms
• Showing how biomolecules conform to physical and chemical laws while enabling the extraordinary properties of living systems

The molecular logic explains both the unity (common chemistry) and diversity (variations in molecular structures) of life across all organisms.

RNA shows greater molecular diversity than DNA in prokaryotes because:

• RNA serves multiple functional roles: mRNA (gene expression), rRNA (ribosome structure), tRNA (translation), and regulatory RNAs
• Each gene produces at least one RNA transcript
• RNA molecules have varying lifespans and exist in different concentrations depending on cellular needs
• RNA undergoes post-transcriptional modifications creating additional species
• Multiple RNA copies can be made from a single DNA gene

In contrast, prokaryotic DNA typically exists as a single circular chromosome (one molecular species), despite containing all genetic information.

This difference highlights the principle that DNA primarily serves as an information storage molecule, while RNA functions as the dynamic operational component of gene expression.

• Geometric isomers result from restricted rotation around a carbon-carbon double bond, which prevents free interconversion between structural arrangements
• In cis isomers, similar groups are positioned on the same side of the double bond (Latin "cis" meaning "on this side")
• In trans isomers, similar groups are positioned on opposite sides of the double bond (Latin "trans" meaning "across")
• These isomers cannot be interconverted without breaking covalent bonds, which requires significant energy input
• Example: Maleic acid (cis) and fumaric acid (trans) have identical chemical formulas but different biological properties due to their distinct spatial arrangements

• Tartaric acid has three stereoisomers: (2R,3R), (2S,3S), and meso-tartaric acid (2R,3S)
• The optically active forms [(2R,3R) and (2S,3S)] are enantiomers (mirror images)
• Meso-tartaric acid (2R,3S) has an internal plane of symmetry
• Key differences:
  • Meso form is optically inactive despite having two chiral centers
  • Meso form is not superimposable on either of the other two forms (it's a diastereomer)
  • Meso form has different physical properties (melting point, solubility) from the enantiomer pair
  • In meso form, the optical rotation effects of the two chiral centers cancel each other
• The meso form can be identified by its symmetrical arrangement where one chiral center is R and the other is S

The stereospecific binding between HIV RNA and small molecules contributes to viral pathogenesis through:

• RNA regulatory regions (like TAR) contain precisely shaped binding pockets that recognize specific protein residues • Arginine-rich domains of viral proteins (like Tat) bind to these RNA pockets with high specificity • This interaction activates viral transcription and replication processes • The binding depends on exact three-dimensional complementarity between the RNA surface and amino acid side chains • Multiple non-covalent interactions (hydrogen bonds, electrostatic interactions) stabilize these complexes

This molecular recognition mechanism allows the virus to:

1. Regulate its gene expression using host cellular machinery
2. Evade immune detection through controlled replication timing
3. Establish persistent infection by modulating viral protein production

This understanding provides targets for antiviral drug development that could disrupt these specific molecular interactions.

Mathematical relationship:

• For any coupled reaction system, ΔGtotal = ΔG1 + ΔG2 + ... + ΔGn
• A coupled reaction will proceed spontaneously when ΔGtotal < 0
• For biological energy coupling: ΔG3 = ΔG1 + ΔG2, where ΔG1 > 0 (endergonic) and ΔG2 < 0 (exergonic)

Essential for metabolism because:

• Cells need to drive thermodynamically unfavorable reactions (synthesis, transport, mechanical work)
• ATP hydrolysis (ΔG ≈ -30.5 kJ/mol) provides the driving force for most endergonic processes
• Without energy coupling, anabolic pathways could not occur
• This principle allows energy released in catabolic pathways to drive specific anabolic processes
• Enables cells to control when and where energetically unfavorable reactions occur

Example: Converting glucose to glucose 6-phosphate would not occur spontaneously, but coupling to ATP breakdown makes it possible and directional.

Structural features ensuring replication fidelity:

• Complementary base pairing (A-T, G-C) provides template specificity
• Hydrogen bond geometry allows only correct pairings
• DNA polymerase has proofreading capability to detect mismatches
• The double helix structure preserves the template during replication
• Sugar-phosphate backbone provides directional constraints (5'→3')

When these mechanisms fail:

• Mutations can occur, altering genetic information
• Substitutions replace one base pair with another (e.g., A-T becomes G-C)
• Insertions or deletions change the reading frame
• Persistent errors can lead to altered protein structures
• Some mutations are silent, while others can affect organism fitness

Example: A rare mismatch during replication (G pairing with T instead of C) that escapes proofreading creates a mutation that could potentially alter protein function in subsequent generations.

Point mutations accumulate through these mechanisms:

• Sequential nucleotide substitutions occur in DNA over generations
• Mutations branch into separate lineages when populations separate
• Each lineage continues to accumulate unique mutations independently
• When two lineages diverge significantly in their genetic makeup that they can no longer interbreed, a new species forms

Example: A gene with sequence TGAGCTA might undergo a G→A mutation, then accumulate additional distinct mutations in separate populations, eventually yielding organisms with incompatible genetic sequences that represent different species.

The Miller-Urey experiment demonstrated:

• Abiotic production of organic compounds (including amino acids) under primitive Earth conditions
• Used spark discharge in a mixture of NH₃, CH₄, H₂, and H₂O at 80°C to simulate early atmospheric conditions
• Proved that biomolecule precursors could form spontaneously without biological processes
• Provided experimental support for the theory that complex organic molecules necessary for life could have formed from simple atmospheric components
• Established a critical step in the chemical evolution that preceded biological evolution

This experiment supports the concept that life could have emerged from non-biological chemical processes under early Earth conditions.

Contributions to understanding abiogenesis:

• Demonstrated that simple organic compounds (amino acids, urea, carboxylic acids) could form abiotically under conditions representing early Earth • Provided empirical support for chemical evolution preceding biological evolution • Established a plausible first step in the pathway from simple chemicals to complex biomolecules • Helped establish the field of prebiotic chemistry

Limitations:

• Only addressed formation of simple organic compounds, not complex polymers or self-replicating systems • The atmospheric composition used (highly reducing, NH₃/CH₄-rich) is now considered different from actual early Earth conditions • Did not explain how molecules could organize into protocells with membranes • Did not address the origin of genetic material or information storage • Created a racemic mixture of molecules, while life uses specific stereoisomers • The high-energy input would likely destroy complex molecules as fast as they formed without protective mechanisms

The experiment represents just one early step in the much more complex process of life's origins, which would have required additional mechanisms for molecular concentration, selection, and organization.