Comprehensive Study Notes on Proteins and Amino Acids

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Proteins: Definition and Biological Importance

Overview of Proteins

Proteins are essential macromolecules found in every cell, forming the structural framework of tissues and organs. They are polymers composed of amino acids linked by peptide bonds. All proteins are constructed from a set of 20 amino acids, which act as the building blocks.

Structural proteins (e.g., collagen, elastin) provide strength and support to tissues.
Enzymes act as biocatalysts, accelerating biochemical reactions.
Defense proteins (antibodies) protect against infections.
Transport proteins (hemoglobin, albumin) carry molecules throughout the body.
Hormonal proteins (insulin, growth hormone) regulate physiological processes.
Contractile proteins (actin, myosin) enable movement.
Storage proteins (ferritin, hemosiderin) store nutrients and ions.
Proteins regulate gene expression, function as ion channels, and stabilize DNA.

Diagram of protein structure as a chain of amino acids linked by peptide bonds

Food Sources Rich in Proteins

Dietary proteins are obtained from both animal and plant sources. Examples include fish, chicken, eggs, cashews, lentils, chickpeas, mung beans, and soybeans. Illustration of various protein-rich foods including fish, chicken, eggs, beans, and milk

Amino Acids: Structure and Classification

General Structure of Amino Acids

Amino acids are the monomers of proteins. Each amino acid consists of a central α-carbon bonded to an amino group (–NH₂), a carboxyl group (–COOH), a hydrogen atom, and a variable side chain (R group).

At physiological pH, the carboxyl group is deprotonated (–COO⁻) and the amino group is protonated (–NH₃⁺).
The chemical properties and biological functions of proteins are determined by the R groups.

General structure of an amino acid with labeled amino, carboxyl, and side chain groups

Essential and Non-Essential Amino Acids

Amino acids are classified based on whether the body can synthesize them.

Essential amino acids: 9 amino acids that must be obtained from the diet (e.g., methionine, threonine, histidine, valine, phenylalanine, isoleucine, tryptophan, lysine, leucine).
Non-essential amino acids: 11 amino acids that the body can synthesize (e.g., alanine, asparagine, glutamate, glutamine, cysteine, glycine, proline, serine, tyrosine, aspartate, arginine).

Mnemonic for non-essential amino acids Mnemonic for essential amino acids

Stereochemistry of Amino Acids

Most amino acids (except glycine) are chiral, possessing an asymmetric α-carbon. They exist as two enantiomers: L- and D-forms.

L-amino acids are incorporated into proteins in living organisms.
D-amino acids are rare and found in some bacterial cell walls and peptide antibiotics.
The configuration is determined by the position of the amino group in the Fischer projection.

Diagram showing the chiral center of an amino acid

Naming and Abbreviations of Amino Acids

Each amino acid has a three-letter abbreviation and a one-letter symbol.

Amino Acid	Three Letter	One Letter
Alanine	Ala	A
Arginine	Arg	R
Asparagine	Asn	N
Aspartic acid	Asp	D
Cysteine	Cys	C
Glutamine	Gln	Q
Glutamic acid	Glu	E
Glycine	Gly	G
Histidine	His	H
Isoleucine	Ile	I
Leucine	Leu	L
Lysine	Lys	K
Methionine	Met	M
Phenylalanine	Phe	F
Proline	Pro	P
Serine	Ser	S
Threonine	Thr	T
Tryptophan	Trp	W
Tyrosine	Tyr	Y
Valine	Val	V

Table of amino acid abbreviations and symbols

Classification Based on R Groups

Amino acids are classified into five main classes based on the properties of their R groups, particularly their polarity.

Nonpolar, aliphatic: Glycine, alanine, proline, valine, leucine, isoleucine, methionine
Aromatic: Phenylalanine, tyrosine, tryptophan
Polar, uncharged: Serine, threonine, cysteine, asparagine, glutamine
Positively charged (basic): Lysine, arginine, histidine
Negatively charged (acidic): Aspartate, glutamate

Table showing classification of amino acids by R group

Acid-Base Properties of Amino Acids

Zwitterion Concept

Amino acids can exist as zwitterions, carrying both positive (amino) and negative (carboxyl) charges in solution.

At neutral pH, amino acids are dipolar ions (zwitterions).
They can act as acids (proton donors) or bases (proton acceptors), making them amphoteric.

Diagram showing zwitterion form of amino acid

Isoelectric Point (pI)

The isoelectric point is the pH at which an amino acid exists as a zwitterion and has a net charge of zero.

The pI can be calculated by averaging the pKa values of the ionizable groups.
At pI, amino acids are least soluble in water and do not migrate in an electric field.

Amino Acids as Precursors of Bioactive Compounds

Neurotransmitters

Certain amino acids serve as precursors for neurotransmitters, which regulate mood, sleep, and other functions.

Tryptophan → Serotonin
Tyrosine → Dopamine, Norepinephrine, Epinephrine
Glutamate → GABA (Gamma-Aminobutyric Acid)

Illustration of neurotransmitter release at a synapse

Hormones

Some amino acids are precursors for important hormones.

Tyrosine → Thyroid hormones (T3 & T4)
Tryptophan → Melatonin

Diagram representing hormone structure

Other Bioactive Molecules

Heme synthesis: Glycine + Succinyl-CoA → δ-Aminolevulinic acid → Heme
Creatine: Arginine + Glycine + Methionine → Creatine (energy storage in muscles)
Glutathione: Glutamate + Cysteine + Glycine → Glutathione (antioxidant)

Structure of glutathione Structure of creatine

Peptides and Peptide Bond Formation

Definition and Types of Peptides

Peptides are molecules formed by linking two or more amino acids via peptide bonds. Types include dipeptides, tripeptides, oligopeptides, and polypeptides. Diagram showing amino acids forming peptides and proteins

Peptide Bond Formation

Peptide bonds form between the α-carboxyl group of one amino acid and the α-amino group of another, releasing a molecule of water. This is a condensation (dehydration) reaction.

Peptide bond (amide linkage) has partial double-bond character due to resonance.
Bond length: ~1.32 Å (between single and double bond lengths).
Peptide bonds are planar and restrict rotation.

Diagram showing peptide bond formation

Cis and Trans Conformations

Peptide bonds can exist in cis or trans forms.

Trans form: α-carbons on opposite sides, more stable, found in most proteins.
Cis form: α-carbons on the same side, rare.

Hierarchy of Protein Structure

Primary Structure

The primary structure is the linear sequence of amino acids in a polypeptide chain, determined by DNA.

Directionality: N-terminal (–NH₃⁺) to C-terminal (–COO⁻).
Each protein has a unique primary structure.
Single amino acid substitutions can cause diseases (e.g., sickle cell anemia).

Diagram showing structure of hemoglobin and sickle cell mutation

Secondary Structure

Secondary structure refers to local folding patterns stabilized mainly by hydrogen bonds.

α-Helix: Right-handed helix, stabilized by hydrogen bonds between C=O and N–H groups.
β-Pleated Sheet: Extended chain, stabilized by hydrogen bonds between adjacent strands. Can be parallel, antiparallel, or mixed.
Loops and Turns: Connect α-helices and β-sheets, often involved in functional regions.

Diagram showing α-helix and β-sheet structures

Tertiary Structure

Tertiary structure is the three-dimensional folding of a single polypeptide chain, resulting in a compact, globular protein.

Stabilized by hydrophobic interactions, hydrogen bonds, ionic interactions, van der Waals forces, and disulfide bonds.
Domains are independent functional units within large polypeptides.
Motifs (supersecondary structures) include β–α–β, β-hairpin, and Greek key motifs.

Quaternary Structure

Quaternary structure is present in proteins with more than one polypeptide chain (subunit).

Subunits may be identical or different.
Held together by non-covalent interactions and sometimes disulfide bridges.
Examples: Hemoglobin (4 subunits), Collagen (triple helix).

Structure of hemoglobin showing subunits and heme groups

Protein Folding and Denaturation

Principles of Protein Folding

Protein folding is the process by which a polypeptide chain attains its native conformation.

Occurs in a stepwise manner, retaining partly correct intermediates.
Molten globule model: domains collapse into compact structures stabilized by hydrophobic interactions.
Enzymes (protein disulfide isomerase, cis–trans proline isomerase) and chaperone proteins (HSPs, chaperonins) assist folding.

Denaturation

Denaturation is the loss of native structure due to disruption of secondary, tertiary, and quaternary structures, while the primary structure remains intact.

Caused by physical (heat, UV, X-rays) and chemical agents (acids, heavy metals, urea).
Results in loss of biological activity, change in solubility, and coagulation.
Denaturation is usually irreversible, but renaturation is possible in some cases.

Methods to Prevent Denaturation

In vitro: Formaldehyde fixation, lyophilisation (freeze-drying).
In vivo: Optimum temperature and pH, buffer systems, chaperone proteins, compartmentalization, protective solutes.

Protein Extraction and Separation Techniques

Overview of Methods

Ion-Exchange Chromatography: Separates proteins based on charge.
Size Exclusion Chromatography: Separates proteins based on size.
Affinity Chromatography: Separates proteins based on specific binding interactions.
SDS-PAGE: Separates proteins based on molecular weight using polyacrylamide gel electrophoresis.

References

Berg, J.M., Tymoczko, J.L., Gatto Jr., G.J. & Stryer, L. (2015) Biochemistry. 8th ed. New York: W.H. Freeman.
Nelson, D., and Cox, M. (2005) Lehninger principles of biochemistry. 4th ed.
Rafi (2020) Biochemistry. 4th ed.