Nucleotides and nucleosides

Nucleic acids (DNA and RNA) are macromolecules that store and transmit genetic information. Their basic building blocks are nucleotides. Each nucleotide contains:

• A five-carbon sugar (ribose in RNA, deoxyribose in DNA)
• A phosphate group (which contributes acidity)
• A nitrogenous base

If the sugar and base are bonded without a phosphate group, the compound is called a nucleoside.

• For example, adenosine (base + sugar) is a nucleoside; adding a phosphate group transforms it into a nucleotide.

Sugar-phosphate backbone

Nucleotides link together through phosphodiester bonds between the phosphate of one nucleotide and the sugar of the next. This creates the sugar-phosphate backbone, which:

• Provides the structural framework of both DNA and RNA
• Positions the bases so they project inward, allowing specific base pairing

Pyrimidine, purine residues

The nitrogenous bases fall into two broad categories:

• Purines: adenine (A), guanine (G), which feature a double-ring structure
• Pyrimidines: cytosine ©, thymine (T), and uracil (U), which contain a single ring
  DNA uses thymine in place of RNA’s uracil.

Deoxyribonucleic acid (DNA): double helix

DNA (deoxyribonucleic acid) lacks an oxygen at the 2′ position on its sugar (hence “deoxy”). It is typically double-stranded:

• According to the Watson-Crick model (building on Rosalind Franklin’s X-ray images), DNA forms a double helix with two complementary strands spiraling around a common axis.
• Base pairing helps ensure replication accuracy:
  • Adenine pairs with thymine
  • Guanine pairs with cytosine

Chemistry

• DNA’s sugar is deoxyribose, missing the 2′$-OH$ group found in RNA’s ribose.
• The phosphate group imparts acidic properties to both DNA and RNA.
• RNA generally remains single-stranded and includes uracil in place of thymine.

Other functions
In addition to storing genetic information:

• Some nucleotides (e.g., ATP) serve as energy currency in cells.
• Certain RNA molecules (like rRNA, tRNA, and mRNA) play key roles in protein synthesis.
• Modified nucleotides can act as cofactors in enzymatic reactions or participate in signaling pathways.

Amino acids

Amino acids are organic compounds and the fundamental building blocks of proteins.
Each amino acid contains:

An amino group ($-N{H}_2$)
A carboxyl group ($-COOH$)
A hydrogen atom ($-H$)
A variable side chain ($-R$)

Most amino acids (except glycine) have a chiral alpha carbon, which means they can exist in different stereochemical forms.

Absolute configuration at the α position
The absolute configuration describes the three-dimensional arrangement of substituents around the amino acid’s alpha carbon. It is designated R or S using the Cahn-Ingold-Prelog rules. Most naturally occurring amino acids are in the L form, and they commonly correspond to the S configuration - except for cysteine, which is L but R by CIP priority (because sulfur has a higher atomic number).

Key points

• Glycine is achiral (its side chain is a second hydrogen).
• Cysteine is typically R since sulfur outranks the carboxyl group in priority.
• D and L notation is based on comparison with the reference molecule glyceraldehyde and does not necessarily match S or R assignments.

Dipolar ions (zwitterions)

Amino acids often exist as zwitterions (dipolar ions) at or near physiological pH. In this form, the amino group is protonated ($-N{H}_3^{+}$) and the carboxyl group is deprotonated ($-CO{O}^{-}$). This dual charge affects:

• Solubility in water
• Interactions with other charged molecules
• Protein folding and stability

The pH at which this dipolar form dominates is the amino acid’s isoelectric point (pI). It is determined by the average of the relevant pKa values.

Classification: acidic or basic

• Acidic amino acids (e.g., aspartic acid, glutamic acid) have side chains that can donate protons and carry a negative charge at physiological pH.
• Basic amino acids (e.g., lysine, arginine, histidine) contain side chains that accept protons, often carrying a positive charge at or near physiological conditions.
  These properties allow amino acids to buffer pH changes in biological systems.

Classification: hydrophilic or hydrophobic

• Hydrophobic amino acids possess nonpolar side chains (e.g., valine, leucine) that typically avoid water.
• Hydrophilic amino acids have polar or charged side chains (e.g., serine, lysine) that readily form hydrogen bonds or electrostatic interactions with water.
  This polarity distinction strongly influences protein folding: hydrophobic side chains tend to cluster inward, while hydrophilic side chains orient toward the aqueous environment.

Synthesis of $\alpha$-amino acids

Amino acids can be synthesized in the laboratory by several methods, most notably:

• Strecker synthesis: Involves the reaction of an aldehyde with ammonium chloride ($N{H}_{4}Cl$) and potassium cyanide ($KCN$), forming an alpha-aminonitrile intermediate, which is then hydrolyzed to yield the amino acid.
• Gabriel synthesis: Utilizes phthalimide as a nitrogen source, which is alkylated and subsequently hydrolyzed to form the free amino acid.

These synthetic methods are often used to obtain racemic mixtures, which can then be resolved to isolate specific enantiomers if desired.

Peptides and proteins: reactions

1. Sulfur linkage for cysteine and cystine

   • Disulfide bonds: Two cysteine residues can form a covalent disulfide bond ($-S-S-$) when their sulfhydryl ($-SH$) groups come into proximity, creating cystine.
   • Importance: These linkages stabilize a protein’s tertiary or quaternary structure by connecting distant parts of a single chain or linking multiple polypeptide chains.

2. Peptide linkage: polypeptides and proteins

   • Formation: Peptide bonds arise from a condensation reaction between the carboxyl group ($-COOH$) of one amino acid and the amino group ($-N{H}_2$) of another, releasing a water molecule.
   • Polypeptides and proteins: Short chains are known as polypeptides, while longer, often more complex chains are referred to as proteins once they fold into functional shapes.

3. Hydrolysis

   • Definition: Hydrolysis breaks peptide bonds, turning polypeptides into smaller fragments or individual amino acids through the addition of water.
   • Methods: This can occur via laboratory treatments (acid or base) or through proteolytic enzymes in biological contexts, essential for protein digestion and turnover.

General principles

1. Primary structure of proteins

   • Linear sequence: The primary structure is the exact order of amino acids in the polypeptide chain, read from the N-terminus to the C-terminus.
   • Importance: This sequence dictates how the chain will fold into higher-level structures.

2. Secondary structure of proteins

   • Localized folding: Secondary structure refers to regional conformations stabilized by hydrogen bonds among backbone $NH$ and $C=O$ groups.
   • Common motifs:
     • $\alpha$ helices: Right-handed spirals with side chains oriented outward.
     • $\beta$ pleated sheets: Extended strands with alternating side chains pointing above or below the sheet plane.

3. Tertiary structure of proteins

   • Three-dimensional folding: Tertiary structure emerges from side-chain interactions such as hydrophobic clustering, ionic bonds, hydrogen bonds, and disulfide linkages.
   • Key components:
     • Proline: Its cyclic side chain introduces bends, disrupting regular helices or sheets.
     • Cystine: Formed by disulfide bonds between cysteine residues, adding robust stability.
     • Hydrophobic bonding: Nonpolar residues cluster inward, shielding themselves from water and driving the overall fold.

4. Isoelectric point

   • Definition: The pH at which a protein or amino acid carries no net charge, often resulting in minimal solubility.
   • Behavior: Around this pH, separation techniques like isoelectric focusing exploit small differences in pI values to differentiate proteins.