Amino Acids, Peptides, and Protein Structure: Study Guide

Amino Acids: Structure, Classification, and Properties

Overview of Amino Acids

Amino acids are the building blocks of proteins, each consisting of a central (α) carbon atom bonded to an amino group, a carboxyl group, a hydrogen atom, and a unique side chain (R group). There are 20 standard amino acids found in proteins, each with distinct chemical properties.

• General Structure: $\mathrm{NH_2{-}CHR{-}COOH}$

• Zwitterion Formation: At physiological pH (~7), amino acids exist as zwitterions, with a positively charged amino group and a negatively charged carboxyl group.

• Chirality: All amino acids except glycine are chiral (have a stereocenter at the α-carbon).

Classification by Side Chain Functional Group

Amino acids are classified based on the chemical nature of their side chains:

• Alkyl: Alanine, Valine, Leucine, Isoleucine

• Alcohol: Serine, Threonine

• Carboxylate: Aspartic acid, Glutamic acid

• Amine: Lysine, Arginine

• Amide: Asparagine, Glutamine

• Thiol: Cysteine

• Thioether: Methionine

• Indole: Tryptophan

• Imidazole: Histidine

• Aromatic: Phenylalanine, Tyrosine, Tryptophan

Classification by Charge and Polarity at pH 7

Negatively charged	Positively charged	Neutral polar	Aliphatic	Aromatic
Asp (D), Glu (E)	Lys (K), Arg (R), His (H)	Ser (S), Thr (T), Asn (N), Gln (Q), Cys (C)	Ala (A), Val (V), Leu (L), Ile (I), Gly (G), Pro (P), Met (M)	Phe (F), Tyr (Y), Trp (W)

Amino Acid Abbreviations

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

Special and Modified Amino Acids

• Selenocysteine: Incorporated during translation, not post-translationally modified.

• Prolyl derivatives: e.g., 4-hydroxyproline, found in collagen.

• Phosphoserine: Involved in signal transduction.

• N-acetyllysine: Role in gene expression suppression.

• γ-carboxyglutamate: Important for Ca2+ binding in blood clotting.

Peptide Bonds and Protein Structure

Formation and Resonance of Peptide Bonds

Peptide bonds are amide linkages formed between the α-carboxyl group of one amino acid and the α-amino group of another. This reaction releases water and forms the backbone of polypeptides.

• Peptide Bond Formation: $\mathrm{Amino\ acid_1{-}COOH + Amino\ acid_2{-}NH_2 \rightarrow Peptide\ bond + H_2O}$

• Resonance: The peptide bond has partial double-bond character due to resonance, restricting rotation and conferring planarity.

Polypeptide Charge and Zwitterions

• At pH 1, polypeptides are positively charged.

• At pH 7, amino acids are typically in their zwitterionic form ($\mathrm{NH_3^+{-}CHR{-}COO^-}$).

• At high pH, both groups are deprotonated.

Protein Sequence and Codons

• Main chain sequence: Written from N-terminus to C-terminus, using generic R for side chains.

• Codons: Triplets of nucleotides in mRNA that specify amino acids. There are 64 possible codons for 20 amino acids.

• Start codon: AUG (methionine).

• Stop codons: UAA, UAG, UGA.

• Special codons: UGA encodes selenocysteine, UAG encodes pyrrolysine.

Protein Cleavage and Enzymes

Proteases and Cleavage Specificity

Proteases are enzymes that hydrolyze peptide bonds, often with specificity for certain amino acid residues.

Enzyme	R1 residue (cleavage site)
Trypsin	Lysine, Arginine (basic residues)
Chymotrypsin	Phenylalanine, Tyrosine, Tryptophan (aromatic residues)
Thrombin	Arginine
V8-protease	Glutamic acid

Digestive Enzymes in Animals

• Trypsin

• Chymotrypsin

• Pepsin

• Additional info: Other common digestive enzymes include elastase and carboxypeptidase.

pKa and Ionization of Amino Acids

pKa Values and Environmental Effects

The pKa of amino acid side chains can vary depending on their environment within a protein. This affects their ionization state and, consequently, protein structure and function.

Group Type	Typical pKa Range
α-Carboxyl	3.5–4.0
Side-chain carboxyl (Asp, Glu)	4.0–4.8
Imidazole (His)	6.5–7.4
Cysteine (–SH)	8.5–9.0
Phenolic (Tyr)	9.5–10.5
α-Amino	8.0–9.0
Side-chain amino (Lys)	9.0–10.4
Guanidino (Arg)	~12

• Environmental Effects: Nearby charged or polar groups can stabilize or destabilize ionized forms, shifting pKa values.

Protein Synthesis and Mutations

Translation and Ribosome Function

• Ribosome: Large complex responsible for protein synthesis using mRNA templates.

• Translation: DNA is transcribed into mRNA, which is then translated into protein sequence.

Mutations and Sequence Homology

• Conservative mutation: Amino acid change that does not significantly affect protein function.

• Nonconservative mutation: Amino acid change that alters protein structure or function.

• Sequence homology: Identical sequences are identical, similar sequences are similar, and homologous sequences share evolutionary ancestry.

Insulin Biosynthesis

Steps of Insulin Biosynthesis

• Preproinsulin: Synthesized as a single polypeptide on membrane-associated ribosomes.

• Signal Peptide: N-terminal sequence directs preproinsulin to the cell membrane.

• Disulfide Bond Formation: Proinsulin is formed by disulfide bonds, then folded and stored.

• Proteolytic Cleavage: Active insulin is generated by cleavage, releasing the mature hormone.

• Active Form: Contains two chains (A and B) held together by disulfide bonds.

Peptide Hormones and Neuropeptides

Gastric Polypeptide Hormones

• GLP-1 (Glucagon-like peptide-1): Involved in glucose metabolism and insulin secretion.

Neuropeptides

• Enkephalin: Modulates pain and stress responses.

• Neuropeptide Y: Regulates appetite and energy balance.

• Neurotensin: Involved in neurotransmission and gastrointestinal function.

• Orexin: Regulates arousal, wakefulness, and appetite.

Summary Table: Amino Acid Properties

Amino Acid	pKa (α-COOH)	pKa (α-NH3+)	pKa (side chain)	Hydropathy Index
Asp	2.1	9.8	3.9	-3.5
Glu	2.2	9.7	4.2	-3.5
His	1.8	9.2	6.0	-3.2
Lys	2.2	9.0	10.5	-3.9
Arg	2.2	9.0	12.5	-4.5
Cys	1.7	10.8	8.3	-1.0
Tyr	2.2	9.1	10.1	-1.3
Ser	2.2	9.2	-	-0.8
Thr	2.1	9.1	-	-0.7
Gly	2.3	9.6	-	-0.4
Ala	2.3	9.7	-	1.8
Val	2.3	9.7	-	4.2
Leu	2.3	9.7	-	3.8
Ile	2.3	9.7	-	4.5
Met	2.1	9.3	-	1.9
Phe	2.2	9.2	-	2.8
Trp	2.4	9.4	-	-0.9
Pro	2.0	10.6	-	-1.6
Asn	2.2	8.8	-	-3.5
Gln	2.2	9.0	-	-3.5

Additional info:

• Surface residues are typically polar or charged (e.g., Asp, Glu, Lys, Arg, His, Ser, Thr, Asn, Gln).

• Interior residues are typically hydrophobic (e.g., Ala, Val, Leu, Ile, Met, Phe, Trp, Pro).

• Peptide bond resonance structures: The bond between C=O and N-H can be represented as a resonance hybrid, with partial double-bond character.

• pKa values can be shifted by the local environment, such as nearby charged groups or hydrogen bonding.

• Insulin biosynthesis involves post-translational modifications and proteolytic processing.