The shape, sequence, and chemical properties of biological macromolecules determine how they behave in cells, influencing processes like signaling, energy storage, and gene expression.
Macromolecules and Their Unique Roles
Biological macromolecules include proteins, carbohydrates, nucleic acids, and lipids, each built from specific monomers and capable of diverse functions. These macromolecules are essential to cell structure and function. This subtopic focuses on the three that are polymers—proteins, carbohydrates, and nucleic acids—emphasizing how their specific molecular structures determine their roles in cells.
The sequence and orientation of monomers determine the 3D structure of a macromolecule.
Structural changes can disrupt or modify molecular function, sometimes resulting in disease.
Common structural features among organisms point to shared evolutionary ancestry and conserved biological roles.
Structure-function relationships in macromolecules are fundamental to understanding everything from gene expression to cellular signaling and metabolism.
Nucleic Acids: Molecular Blueprint and Its Directionality
Structural Characteristics
Nucleic acids are made up of nucleotide monomers, each consisting of three components:
A five-carbon sugar: deoxyribose in DNA or ribose in RNA.
A phosphate group, which links nucleotides together.
A nitrogenous base: adenine (A), thymine (T), cytosine (C), guanine (G) in DNA; uracil (U) replaces thymine in RNA.
These nucleotides are connected by phosphodiester bonds between the 5' phosphate of one nucleotide and the 3' hydroxyl group of the next.
Image courtesy of Lumen Learning
Directionality
Nucleic acids exhibit directionality, with distinct 5' and 3' ends.
Synthesis occurs in the 5' to 3' direction, meaning nucleotides are added to the 3' end.
The template strand during transcription is read 3' to 5', so RNA is made 5' to 3'.
This directionality is critical for accurate DNA replication and RNA transcription. It ensures enzymes like DNA polymerase and RNA polymerase operate correctly and that base pairing remains consistent.
Double-Stranded DNA and Base Pairing
DNA is composed of two antiparallel strands held together by hydrogen bonds.
One strand runs 5' to 3'; the other runs 3' to 5'.
Bases pair specifically: adenine pairs with thymine via two hydrogen bonds, and cytosine pairs with guanine via three hydrogen bonds.
This base pairing is essential for the complementarity needed during replication and transcription. The helical shape of DNA (double helix) adds stability and protects the sequence.
RNA and Functionality
RNA, being single-stranded, folds into various secondary structures that give it diverse functions:
mRNA carries the genetic message from DNA to ribosomes.
tRNA delivers amino acids during translation.
rRNA forms the structural core of ribosomes.
Regulatory RNAs (e.g., miRNA) modulate gene expression.
The sequence and shape of RNA molecules directly determine their roles in these processes.
Image courtesy of BioNinja
Proteins: From Amino Acid Sequence to Cellular Machinery
Amino Acid Structure and Polymerization
Proteins are composed of amino acids, each consisting of:
An amino group (–NH2)
A carboxyl group (–COOH)
A hydrogen atom
A variable R group (side chain)
A central carbon atom (alpha carbon)
Amino acids are linked through peptide bonds, formed via dehydration synthesis between the carboxyl group of one amino acid and the amino group of the next. This reaction releases a molecule of water.
Primary Structure and Its Importance
The primary structure is the linear sequence of amino acids in a protein. This sequence is encoded by the nucleotide sequence in DNA.
The order of amino acids determines how the protein will fold.
Even a single substitution (e.g., valine instead of glutamic acid in hemoglobin) can disrupt folding and result in diseases such as sickle cell anemia.
Higher Levels of Protein Structure
Proteins fold into specific shapes necessary for their function through multiple structural levels:
Secondary Structure:
Local folding of the polypeptide chain into structures such as alpha helices and beta-pleated sheets.
Stabilized by hydrogen bonds between the backbone (not side chains).
Tertiary Structure:
The 3D folding of the entire polypeptide, including:
Hydrophobic interactions: Nonpolar side chains cluster inside.
Hydrogen bonds: Between polar side chains.
Ionic bonds: Between charged R groups.
Disulfide bridges: Covalent bonds between sulfur atoms in cysteine side chains.
Van der Waals interactions: Weak attractions between close atoms.
Quaternary Structure:
Formed when two or more polypeptide chains assemble into a functional protein.
Examples include hemoglobin and DNA polymerase.
Each level of structure builds upon the last, and any disruption can cause misfolding or loss of function.
Image courtesy of Lumen Learning.
Protein Denaturation
Denaturation occurs when a protein loses its tertiary and quaternary structure due to external factors:
Heat
pH shifts
Salt concentration changes
Chemical exposure
Denaturation does not break peptide bonds, so the primary structure remains. However, the loss of 3D shape causes loss of function. Denatured enzymes, for example, cannot bind substrates or catalyze reactions.
Carbohydrates: Structure and Energy Roles
Monosaccharides and Disaccharides
Monosaccharides are the simplest sugars (e.g., glucose, fructose). They can form disaccharides via glycosidic bonds:
Maltose: glucose + glucose
Sucrose: glucose + fructose
Lactose: glucose + galactose
Glycosidic bonds are formed by dehydration synthesis and broken by hydrolysis.
Image courtesy of ResearchGate
Polysaccharides and Structure
Polysaccharides are long chains of monosaccharides with different structures depending on linkage type:
Starch: Alpha-1,4 and alpha-1,6 linkages; energy storage in plants.
Glycogen: Highly branched alpha-linkages; energy storage in animals, especially in liver and muscle cells.
Cellulose: Beta-1,4 linkages; structural polysaccharide in plant cell walls. Humans cannot digest this.
Chitin: Modified cellulose with nitrogen groups; structural component in fungi and arthropods.
Structural and Functional Diversity
Linear polysaccharides (e.g., cellulose) form rigid structures.
Branched polysaccharides (e.g., glycogen) are compact and rapidly mobilized for energy.
Glycosidic bond positioning and branching affect:
Solubility
Enzyme accessibility
Digestibility
Carbohydrates also decorate proteins and lipids on the cell surface, forming glycoproteins and glycolipids involved in cell-cell recognition, immune responses, and signaling.
Predicting Function Based on Molecular Structure
Understanding a molecule's structure allows predictions about its behavior in cells:
A protein with a nonpolar core and polar surface will likely be soluble in water.
A carbohydrate with beta-linkages is likely structural and indigestible for many animals.
A nucleic acid strand running 5' to 3' indicates the direction of replication and transcription.
Example: Sickle Cell Disease
Normal hemoglobin has glutamic acid at position 6 in the beta chain.
In sickle cell anemia, this is replaced with valine, a hydrophobic amino acid.
This causes hemoglobin to aggregate under low oxygen, distorting red blood cells into a sickle shape.
These cells can block blood flow, causing pain, fatigue, and organ damage.
This single substitution exemplifies how a minor structural change can lead to major functional consequences.
Directionality in Macromolecules
Proteins
Synthesized from the N-terminus to the C-terminus.
Enzymes interact with the polypeptide chain in a direction-specific manner.
Protein domains often function in a directional way—N-terminal domains may be signal peptides, while C-terminal regions could anchor proteins in membranes.
Nucleic Acids
DNA and RNA synthesis occurs 5' to 3'.
Regulatory elements like promoters are located upstream (5') of genes.
Translation reads mRNA in a directionally defined reading frame, which ensures the correct amino acid sequence.
Carbohydrates
Enzymes are specific to the orientation of glycosidic bonds.
Alpha-amylase breaks down alpha-1,4 bonds in starch, but not beta-1,4 bonds in cellulose.
Directionality determines how molecules are built, broken down, and recognized by other molecules.
Evolutionary Conservation of Macromolecular Structure
Macromolecular structures are conserved across species, reflecting shared ancestry and evolutionary pressure to maintain function.
Proteins like cytochrome c have similar amino acid sequences across animals.
Structural motifs like beta-barrels, zinc fingers, and helix-turn-helix domains are found in diverse proteins with conserved functions.
DNA and RNA polymerases share structural similarities between prokaryotes and eukaryotes.
Such conservation allows scientists to study proteins in model organisms and apply findings to humans.
Interactions Between Macromolecules
Macromolecules frequently interact to perform complex cellular tasks:
Protein-DNA interactions: Transcription factors bind specific sequences to regulate gene expression.
Protein-RNA interactions: Ribosomal proteins interact with rRNA during translation.
Protein-carbohydrate interactions: Surface proteins bind specific sugars on pathogens or neighboring cells.
Lipid-protein interactions: Membrane proteins require the correct lipid environment to function.
These interactions depend on complementary shape, charge, and chemical affinity, all determined by the molecules' structures.
Molecular Complexes
Nucleosomes: DNA wrapped around histone proteins for efficient packaging.
Enzyme complexes: Sequential enzymes in a pathway form multi-enzyme complexes to increase efficiency.
Signal transduction pathways: Chains of protein-protein interactions relay messages from cell surface to nucleus.
All of these systems rely on precise structural compatibility to function correctly. A mutation affecting even one interaction site can disrupt an entire pathway.
FAQ
Mutations in nucleic acids, particularly in DNA, can alter the nucleotide sequence of a gene, which may change the amino acid sequence of the resulting protein. This change can affect the protein’s folding, shape, and function. A point mutation (a single base substitution) can result in:
Silent mutation: No change in the amino acid (due to codon redundancy).
Missense mutation: One amino acid is replaced by another, possibly altering protein function.
Nonsense mutation: A stop codon is introduced prematurely, shortening the protein.
Even a single amino acid change, such as in sickle cell disease, can drastically impair function.
The R groups, or side chains, of amino acids differ in size, polarity, and charge, and they determine how the protein folds into its tertiary structure. These interactions between R groups include:
Hydrophobic interactions: Nonpolar R groups cluster in the protein’s interior.
Hydrophilic interactions: Polar R groups remain on the surface, exposed to water.
Ionic bonds: Between positively and negatively charged R groups.
Disulfide bridges: Covalent bonds between cysteine residues for added stability.
Hydrogen bonding: Between polar R groups, helping stabilize folding.
These interactions shape the protein’s final 3D structure and determine its ability to interact with specific molecules like substrates or receptors.
The degree of branching in polysaccharides affects their solubility, compactness, and rate of enzymatic breakdown. Branched polysaccharides, like glycogen and amylopectin, offer more accessible ends for enzymatic activity, which allows for:
Rapid mobilization of glucose when energy is needed quickly.
Efficient packing within cells for energy storage.
Increased solubility, making them easier to distribute within aqueous environments.
In contrast, unbranched polysaccharides like cellulose are better suited for structural support because the long, linear chains form rigid fibers through hydrogen bonding between adjacent chains, offering strength and durability.
DNA strands run in opposite directions—one 5' to 3', the other 3' to 5'—which is known as antiparallel orientation. This configuration is essential because:
It allows for complementary base pairing (A with T, G with C) through hydrogen bonds.
It enables the enzyme DNA polymerase to add nucleotides only to the 3' end during replication.
It ensures that transcription occurs correctly, as RNA polymerase also reads the template strand 3' to 5'.
Without antiparallel strands, accurate replication and gene expression wouldn’t be possible, as base pairing and polymerase action depend on correct strand alignment.
Proteins often contain specific structural domains—distinct regions within their tertiary or quaternary structure—that carry out specialized tasks. These domains contribute to:
Binding: For example, the SH2 domain binds phosphorylated tyrosines, common in signaling proteins.
Catalysis: Enzyme active sites are located within well-defined catalytic domains.
Transport: Transmembrane domains help anchor proteins within cell membranes and transport substances.
Flexibility and interaction: Modular domains like zinc fingers or leucine zippers help in DNA binding and protein-protein interactions.
Each domain functions semi-independently but contributes to the overall activity of the protein. Mutations within specific domains can impair only one aspect of the protein’s role without affecting the entire molecule.
Practice Questions
Explain how the specific structure of DNA enables it to carry out its function in genetic information storage and transmission.
DNA’s structure is ideal for storing and transmitting genetic information. It is a double-stranded helix composed of nucleotide monomers, each with a sugar, phosphate group, and nitrogenous base. The strands run antiparallel, with base pairs (A–T and G–C) joined by hydrogen bonds, ensuring stability and accurate replication. The sequence of bases encodes genetic instructions, and the uniform width of the helix allows tight packaging in chromosomes. During replication, the strands separate, and each serves as a template for a new complementary strand. Directionality (5’ to 3’) and complementary pairing ensure high fidelity in information transmission.
Describe how a change in protein primary structure can affect its function, using a specific example.
A change in the primary structure of a protein alters its amino acid sequence, which can impact folding and overall function. For example, in sickle cell disease, a single amino acid substitution—valine replaces glutamic acid at the sixth position in the beta chain of hemoglobin—changes the protein’s structure. This substitution causes hemoglobin molecules to stick together under low oxygen conditions, forming rigid fibers that distort red blood cells into a sickle shape. These misshapen cells block blood flow and break easily, leading to reduced oxygen delivery and anemia. This example shows how one small change can impair protein function dramatically.
