BIOCHEMISTRY 08/20/2019

Amino Acids, Peptides & Protein Structures Shifting 01

Trans 02
[SUBJECT]
Dr. Phylis C. Rio
[Name of Lecturer]
OUTLINE Table 1. Names and abbreviations of common Amino Acids

I. AMINO ACIDS
[SUBJECT]IV. CHEMICAL REACTIONS Alanine Ala A
A. Structure of Amino OF AMINO ACIDS Arginine Arg R
Acids [Name of Lecturer] A. Carboxyl Group Asparagine Asn N
II. CLASSIFICATION OF B. Amino Group Aspartic Acid Asp D TIPS TO MEMORIZE LETTERS:
AMINO ACIDS C. Side Chain Cysteine Cys C
A. Structure[SUBJECT]
Arginine →Rginine
D. Special Functions of Glutamic Acid Glu E Aspartic Acid→AsparDic Acid
B. Side Chain Amino Acids Glutamine Gln Q Glutamic Acid→GlutamEc Acid
C. Metabolic[Name
Fate of Lecturer]
V. PROTEINS Glycine Gly G Glutamine→Qutamine
D. Nutritional Requirement A. Peptide Bonds Histidine His H Phenylalanine→Fenylalanine
III. PROPERTIES OF AMINO B. Protein Structures Isoleucine Ile I Tryptophan→Wyphtophan
Leucine Leu L Tyrosine →TYrosine
ACIDS C. Protein Folding
Lysine Lys K
A. Acid-Base D. Complex Proteins Threonine – alphabetically it
Methionine Met M
B. Isoelectric Point VI. CLINICAL SIGNIFICANCE Phenylalanine F F
comes first among the 3 amino
C. Optical Property acids that start with letter “T” so it
Proline Pro P should have T as its abbreviation
Serine Ser S
I. AMINO ACIDS Threonine Thr T
▪ Building blocks of proteins Tryptophan Trp W
▪ 300 known amino acids Tyrosine Tyr Y
▪ 20 commonly occurring in proteins Valine Val V
▪ Most are α-amino acids (except proline: imino acid)
→ Imino acid: no free amino group since its amino group II. CLASSIFICATION OF AMINO ACIDS
is attached to the R-group
▪ Amino group is attached to same carbon atom to which A. STRUCTURE
carboxyl group is attached ▪ Aliphatic amino acid – linear/branched; acyclic
▪ Designated three letter abbreviation or a one letter symbol
➔ Monoamino, monocarboxylic (acid)
▪ Selenocysteine - “21st amino acid”
• Linear chain: glycine, alanine
·Inserted in protein during translation but not specified
by codon • Branched chain: valine, leucine, isoleucine
·Selenium replaces sulfur in cysteine • Hydroxylic(-OH): serine, threonine, tyrosine
·Peroxides & reductants, involved in electron transport • Sulfur-containing: cysteine, methionine
• Amino acid of carboxymide group: asparagine,
glutamine
A.STRUCTURE OF AMINO ACIDS
➔ Monoamino, dicarboxylic (acid) [D,E]
▪ Alpha carbon: where R groups attach • Aspartic acid (aspartate), glutamic acid (glutamate)
▪ Hydrogen atom (-H) ➔ Diamino, monocarboxylic (basic)
▪ Carboxyl group (-COOH) • Lysine, arginine, histidine [H,A,L]
▪ Amino group (-NH2) ▪ Aromatic amino acid/heterocyclic – cyclic
▪ Side chain (-R): varies per amino acid • Ring containing
• Phenylalanine, tyrosine, tryptophan, histidine
[W,H,Y,F]
▪ Imino acid
• Proline
- Aliphatic cyclic structure
- Amino group is considered as a secondary
amine because the nitrogen is bonded to 2
carbon atoms
B. SIDE CHAIN
Fig. 1. Basic structure of an amino acid (Mark)
▪ Amino acids with non-polar side chain
·At a physiologic pH (7.4), the amino group on these amino - Electrons are equally shared between carbon and
acids carries a positive charge, and the carboxylic acid group hydrogen atoms in side chain
is negatively charged. At pH values much lower than the pKa - cannot form hydrogen bonds
(higher hydrogen ion concentrations), all of the carboxylic acid - Some are highly hydrophobic in water
groups are protonated. - Glycine, alanine, valine, leucine, isoleucine,
·Zwitterion: ions in which the amino group is positively charged methionine, proline, phenylalanine, tryptophan,
and the carboxylate group is negatively charged tyrosine (not hydrophobic at certain pH)
▪ Amino acids with uncharged/non-ionic polar side chain
(neutral)
- Hydrophilic in nature
- Serine, threonine, tyrosine, cysteine, glutamine,
asparagine
- Amide group of asparagine and glutamine
- OH group in serine, tyrosine, and threonine
- Sulfur in cysteine can form disulfide bond

BCHM Espino, Halili, Necosia, Valad-on 1 of 13

 ▪ Amino acid with charged ionic polar side chain
- Most are hydrophilic in nature
- Acidic amino acids with negative (-) charges in the R
group: aspartic acid, glutamic acid
- Basic amino acids with positive (+) charges in the R
group: lysine, arginine, histidine
▪ Hydrophobic: any formed, interior of protein; cannot interact
with outside environment
▪ Hydrophilic: any formed, exterior of protein

Table 2. Hydrophilic and Hydrophobic Amino Acids

Hydrophilic Hydrophobic
Arg Ala
Asn Ile
Fig. 2. Metabolic fates of amino acids
Asp Leu
Cys Met
D. NUTRITIONAL REQUIREMENT
Gln Phe
▪ Essential amino acids
Glu Pro
- Their carbon skeleton cannot be synthesized by human
Gly Trp body and are supplied by diet
His Tyr - Isoleucine, leucine, Lysine, threonine, methionine,
Lys Val phenylalanine, tryptophan, valine
Ser - [V MILK FTW]
Thr ▪ Semi-essential amino acids
- Not essential in adult but essential to children
- Histidine, arginine [HR]
● Special groups in side chains of amino acids: ▪ Non-essential amino acid
·Arginine – guanidium - 10 amino acids
·Phenylalanine – benzene ▪ Derived amino acid after enzymatic reaction
·Tyrosine– phenol ➔ Derived amino acid found in protein
·Tryptophan– indole ·Ex. Hydroxyproline
·Histidine – imidazole ➔ Derived amino acid not seen in protein
·Proline – pyrrolidine ·Ex. Ornithine, citrulline
➔ Non- α amino acid
·Ex. Gamma amino butyric acid (GABA) derived
C. METABOLIC FATE
from glutamic acid
▪ Ketogenic amino acid
- when metabolize can give acetoacetate or its Table 4. Amino Acids Requirements of Humans
precursors (acetyl-coA and acetoacetyl-coA) that Nutritionally Notionally Non-
can be used as ketone bodies Essential essential
- Leucine, lysine [L,K] Arg1 Ala
▪ Glucogenic amino acid
His1 Asp
- Pyruvate and the intermediates of citric acid cycle
Ile Asn
- Purely glucogenic: other 14 amino acids
▪ Ketogenic and glucogenic Leu Cys
- Isoleucine, tyrosine, phenylalanine, tryptophan [W,I,F,Y] Lys Glu
Met Gln
Phe Gly
Table 3. Fate of the Carbon Skeletons of the Protein L-α-Amino Acids Thr Hydroxyproline2
Trp Hydroxylysine2
Val Pro
Converted to Amphibolic Intermediates That
Ser
Form
Tyr
Carbohydrate Fat Glycogen
(glucogenic) (ketogenic) and fat
(glucogenic 1
Semi-essential: synthesized at rates inadequate to support growth of
and children.
ketogenic) 2
Not necessary for protein synthesis, but is formed during post-
Ala Gln Leu Ile translational processing of collagen.
Arg His Lys Tyr
Asn Met Phe III. PROPERTIES OF AMINO ACIDS
Asp Pro Trp
Cys Ser A. ACID-BASE
Glu Thr - Amphoteric or ampholytes (both acid and base)
Gly Val - The α-COOH and α-NH2 groups are capable of ionizing
(removal of ion)
- α-amino group → basic part
- α-COOH → acidic part
- ionization states primarily depend on pH of the environment

BCHM Amino Acids, Peptides, & Protein Structures 2 of 13

 - ACIDIC ENVIRONMENT (low pH) Example of typical pI problem
o An environment with abundant H+ ions (See appendix for the whole reaction mechanism)
o Amino group is protonated (NH2 → NH3+) ▪ Amino Acid: Lysine
o Carboxyl group remains as COOH (H+ is not dissociated) ▪ Has +2 net charge in acidic environment
o Net charge: POSITIVE ▪ Order of H+ removal:
-
BASIC ENVIRONMENT (high pH) o Carboxyl group H+
o An environment with low H+ ions o α-Amino group H+
o Amino group remains as NH2 o Side chain (-NH3) H+
o Carboxyl group is deprotonated (H+ is removed)
o Net charge: NEGATIVE
- AT PHYSIOLOGICAL pH 7.4
o Carboxyl group is deprotonated (-)
o Amino group is protonated (+)
o Net charge: ZERO
- Acid strength is measure by Ka (higher value means stronger
acid)
o An acid is considered as a strong acid if it can readily
give off/donate its H+
o pKa = -log (Ka)
→ pKa and Ka are inversely proportional
→ higher Ka = lower pKa
→ high Ka = strong acid
→ low pKa = strong acid Fig. 3. Structure of Histidine

B. ISOELECTRIC POINT 𝑝𝐾𝑎2 + 𝑝𝐾𝑎3 𝑝𝐾𝑁𝐻3 + 𝑝𝐾𝑅 8.95 + 10.53

𝑝𝐼 = = = = 9.74
▪ Isoelectric point (Pi) 2 2 2
-The pH between the pKa values for the ionization on either
side of the isoelectric species (in between zwitterion)
▪ Zwitterion Example of atypical pI problem
-Dipolar at physiological pH 7.4 (See appendix for the whole reaction mechanism)
-No net charge (equal amount of + and – charges) ▪ Amino Acid: Histidine
-When the net charge of an amino acid is zero, the pH will be
equivalent to the isoelectric point (pI) → In histidine, the imidazole side chain contributes
-No mobility in an electric field to the titratable group
-Solubility and buffering capacity will be minimum → Order of H+ removal:
- The charges from the dissociable functional groups of Carboxyl group
amino acids ensure that they are readily solvated by polar R group
solvents but insoluble in nonpolar solvents Amino Group
-Varying the pH of the environment facilitates physical → At low pH (acidic) histidine has a net +2 charge
separation of amino acids, peptides and proteins because of the amino group and nitrogen from
• Non-polar environment: the imidazole ring
- Possesses less capacity to stabilize charged species → In an acidic environment there are more H+ thus
- Raises pKa of Carboxyl groups making it a weaker it favors protonation of carboxyl, amino and R
acid groups
-Lowers pKa of amino groups making it a stronger acid → As base is added/pH increases (basic) the
-Presence of adjacent oppositely charged group stabilizes a carboxyl group loses an H+ (becomes a
developing charge (attraction) carboxylate) and the net charge of histidine
-Presence of adjacent similarly charged group destabilizes a becomes +1
developing charge (repulsion) → As pH increases, H+ of the R group is removed
and net charge becomes 0 (zwitterion)
How to solve pI problems → Then, the last H+ to be removed is from the
• Rules: amino group and net charge becomes (-1)
- see pKa values of each ionizable H+ of the carboxyl group,
amino group and R group
- sequence of removal is from the lowest pKa to the 𝑝𝐾𝑎2 + 𝑝𝐾𝑎3 𝑝𝐾𝑅 + 𝑝𝐾𝑁𝐻3 9.17 + 6.00
𝑝𝐼 = = = = 7.59
highest pKa (stronger acid to the weakest acid) 2 2 2
- start from acidic to basic environment / titration
- use the pKa values before and after the zwitterion (amino
C. OPTICAL PROPERTY
acid with no net charge) in solving for pI
→ Amino acids are chiral except glycine
▪ Chiral - the tetrahedral carbon is attached to 4 different
substituents (maximum bond of Carbon is 4); Non-
superimposable mirror image
o Glycine is not chiral since there are 2 hydrogen atoms
- Typical order of H+ removal: attached to the α-carbon
o carboxyl group H+ (lowest pKa) o Chiral molecules have active optical property
o Amino group H+ ▪ All amino acids are in L-configuration
o R group H+ (highest pKa) o All amino acids share the absolute configuration of L-
- Atypical order of H+ removal: glyceraldehyde
o Carboxyl group H+ (lowest pKa) o The biochemical reactions of L-α-amino acids and their
o R group H+ precursors are catalyzed by enzymes that act
o Amino group H+ (highest pKa) exclusively on L-isomers
* The R group H+ is ionized first in some cases o L-amino acids participate in cellular functions as
because it has a lower pKa value than that of diverse as nerve transmission and biosynthesis of
the amino group (C,H,E,D) porphyrins, purines, pyrimidines and urea

BCHM Amino Acids, Peptides, & Protein Structures 3 of 13

 o Methionine + methyl group acceptor →
▪ D-amino acids homocysteine
o found mainly in nature as synthetic compounds like
antibiotics (Bacitracin, Gramicidin A & Bleomycin)
• Ester formation
▪ Amino acids do not absorb visible light thus they are - Involves the hydroxyl group
colorless - Hydroxyl-containing amino acids (serine, threonine,
o Aromatic amino acids (tryptophan, tyrosine and tyrosine) can form esters with phosphoric acid, forming
phenylalanine) can absorb UV light in the range of 280
phosphoproteins
nm
o Ability of protein to absorb UV light is due to the - Similarly, these hydroxyl groups can form O-glycosidic
presence of predominant tryptophan monomers bonds with carbohydrate residues to form
glycoproteins
• Reaction of Amino group
IV. CHEMICAL REACTIONS OF AMINO ACIDS - Amide groups of glutamine and asparagine
can form N-glycosidic bonds with
A. CARBOXYL GROUP carbohydrates to form glycoproteins
• Decarboxylation • Reactions of –SH groups
- Removal of carboxyl group (-COO) - Sulfur-containing amino acids (methionine,
- For production of important amines cysteine) can bond with another sulfur-
- The enzymes that catalyze this reaction are called containing compound, forming a disulfide
decarboxylases bond (S-S)
o Histidine (His) decarboxylation → Histamine - The dimer formed by two cysteine residues is
o Tyrosine (Tyr) decarboxylation → Tyramine called dicysteine or cystine
• Amide formation (carboxylation)
- The carboxyl group of a dicarboxylic amino acid D. SPECIAL FUNCTIONS OF AMINO ACIDS
(Aspartic acid and Glutamic acid), other than the α- • As neurotransmitters: gamma-aminobutyric acid (GABA) is
carboxyl group, can combine with ammonium (NH3) derived from glutamine, while dopamine is derived from
- This reaction requires high energy and are mostly done tyrosine
by enzymes called synthetases • Histamine (from His) serves as a mediator of allergic
o Aspartic acid + NH3 → Asparagine reactions
o Glutamic acid + NH3 → Glutamine • As a hormone: Thyroxine, derived from tyrosine, is a thyroid
hormone
B. AMINO GROUP • Histidine: important buffering activity, found in reactive
• Transamination center of enzymes, can donate or accept electrons
- The α-amino group can be transferred to an α-keto • Lysine: binding of coenzymes like pyridoxal phosphate and
acid to form a new amino acid and an α-keto acid biotin (involved in carboxylation)
- Important reaction in the body for the interconversion of • Ornithine and citrulline: derived from Arginine (Arg);
amino acids and for synthesis of nonessential amino essential in urea synthesis
acid • Nitric oxide, also derived from Arg, is a smooth muscle
- Amine transfers are usually facilitated by pyridoxal relaxant
phosphate (PLP) • Serotonin, Melatonin and Niacin – derived from tryptophan
o Glutamic acid + pyruvate → α-ketoglutarate + (Trp)
alanine
• Oxidative deamination
V. PROTEINS
- Removal of the α-amino group from its α-carbon
- Could be done thru oxidative (Redox) or non-oxidative • Physically and functionally complex macromolecules with
(via specific enzymes) reactions nitrogenous compounds
o Glutamic acid is the most common and • Made up by polymerization of amino acids through peptide
bonds
important amino acid that undergoes this
reaction Table 5. Function of Different Proteins
• Carbamino/carbamate formation Protein/Related System Function
- CO2 is added to a free amino group to form a Cytoskeleton Cell shape
carbamate Actin and Myosin Contraction
- Occurs at alkaline pH and serves as a mechanism for Hemoglobin O2 transport, buffer
the removal of CO2 from the tissues and lungs by Antibody Defense
hemoglobin Enzyme Catalysis
Hormone Regulatory
Collagen, Keratin, Elastin Structural
Lipoprotein/Albumin Lipid transport
C. SIDE CHAIN GABA Neurotransmitters
• Transmethylation Gramicidin A Antibiotic
- Methyl group of methionine after activation by ATP Bleomycin Ant-tumor agent
(activated form: S-adenosylmethionine/SAM) is
transferred to an acceptor which becomes methylated
and forms homocysteine

BCHM Amino Acids, Peptides, & Protein Structures 4 of 13

 • By convention, N-terminal end is written at the left while the C-
terminal and is written at the right
• Some peptides contain unusual amino acids
→ In mammals, peptide hormones usually only contain the α-
amino acids linked by standard peptide bonds, however,
other peptides may contain non-protein amino acids,
derivatives of the protein amino acids, or amino acids linked
by an atypical peptide bond.
▪ Ex. The amino terminal glutamate of glutathione, which
participates in protein folding, is linked to a cysteine by a
non-peptide bond.
• The peptide bond has partial double-bond character
→ Proteins, despite the presence of single bond, exhibits a
partial double-bond character, hence, the bond that connects
a carbonyl carbon to the α-nitrogen cannot rotate
→ Rigid and planar
▪ O, C, N, and H atoms of a peptide bond are coplanar
→ The imposed semi-rigidity of peptide bonds has important
consequences in which peptides and proteins fold to
Figure 4. Life cycle of a hypothetical protein (Rodwell et.al, 2018,
generate higher orders of structure.
p. 76)
1. Cycle begins with synthesis on a ribosome of a polypeptide
chain whose primary structure is dictated by an mRNA
2. Polypeptide begins to fold into its native conformation
3. Folding may be accompanied by processing events such as
proteolytic cleavage of an N-terminal leader sequence (Met-
Asp-Phe-Gln-Val) or formation of disulfide bonds (S – S)
4. Subsequent covalent modifications may, for example, attach a
fatty acid molecule (yellow) for (5)
5. Translocation of the modified protein to a membrane
6. Binding an allosteric effector may trigger the adoption of a Figure 6. Partial double bond character of a peptide bond
catalytically active conformation (Rodwell et.al, 2018, p. 71)
7. Proteins get damaged by chemical attack, deamidation, or
denaturation over time
8. They may be “labelled” by the covalent attachment of several
ubiquitin molecules (Ub)
9. Ubiquitinated protein is degraded to its component amino
acids, which become available for the synthesis of new
proteins
A. PEPTIDE BONDS
• Peptide
→ Unbranched short chain of amino acids
→ Each joined to the next by a peptide bond
▪ Dipeptide – two (2) amino acids joined together by one
(1) peptide bond
▪ Oligopeptide – three (3) to ten (10) amino acids
▪ Polypeptide – more than ten (10) amino acids
• Peptide bond formation
→ the most important reaction of amino acids
→ formed when alpha carboxyl group of one amino acid
reacts and condenses with alpha amino group of another
amino group with loss of water (dehydration)
→ also called amide bond
→ a covalent bond resulting to stable sharing of electrons
→ CO-NH bridge
• Protein – long chain of amino acid
Figure 7. Dimensions of a fully extended polypeptide (Rodwell,
et.al, 2018, p. 71)
• Trans in nature (except proline)
→ Trans configuration – R groups are on opposite sides of an
imaginary reference line on the molecule
• Side chains are free to rotate on the either side of peptide bond
• Peptides are Polyelectrolytes
→ At any pH of physiologic interest, the peptide bond is
uncharged. Therefore, formation of amino peptides from
amino acids is accompanied by a net loss of one positive and
one negative charge per peptide bond.
→ Peptides are charged molecules at physiologic pH owing to
their -COOH and -NH3 terminal groups and where present,
Figure 5. Formation of Peptide Bond (wps.prenhall.com) their acidic R or basic R groups.

BCHM Amino Acids, Peptides, & Protein Structures 5 of 13

 ▪ For amino acids, the net charge on a peptide depends on → Example:
the pH of its environment and on the pKa values of its • In normal hemoglobin (Hb A), the amino acid in the beta
dissociating groups. chain is glutamic acid. In sickle cell anemia, glutamic acid
is changed to valine
B. PROTEIN STRUCTURES
• Regular conformations in Protein:
• Configuration → Globular: compactly folded and coiled
→ Geometric relationship between a given set of atoms ▪ Proteins with catalytic, regulatory, and transport functions
→ Rearrangement requires breakage of covalent bonds (w/ → Fibrous: more filamentous or elongated
rupture) ▪ Proteins with structural and contraction functions
→ Example: L- and D- amino acids
• Conformation
→ Spatial relationship of every atom in a molecule
→ 3D arrangement
→ Interconversion between conformers occurs without covalent
bond rupture
▪ Retention of configuration
▪ Typically via rotation about a single bond

Figure 9. Structure of a polypeptide chain

(images.tutorvista.com)

Secondary Structure
• Regularly repeating types of structures
• Hydrogen bond
→ Stabilizes and maintains the secondary structure
→ Between carbonyl group of one amino acid to amide group
of another amino acid
→ Occurs between one of the lone pairs on an oxygen atom of
carbonyl group and the hydrogen attached to a nitrogen
group

Figure 8. Levels of Protein Structure Organization Figure 10. Secondary structure (alpha helix) with hydrogen
(bio.libretexts.org) bonds (desertbruchid.net)
• Conformations of secondary structure
Primary Structure 1. Alpha Helix (α-helix)
• Denotes the number and sequence of amino acids in a protein → Polypeptide chain is twisted to form a coiled/spiral/rod-like
(linear) structure
• Polymerization of amino acids → polypeptide chain ▪ Tightly coiled backbone forms the inner part and side
→ Each amino acid in the chain is called residue chains extend outward
→ Linkage is maintained by peptide bond → Common structure of globular class
• Basis of higher levels of organization → Right-handed conformation – more stable
• Determines structure and biologic activity of protein → Intrachain hydrogen bonds
→ A polypeptide chain has a unique amino acid sequence ▪ Carbonyl carbon (CO) of one amino acid forms H bond
decided by the gene sequence encoded in the genetic code with amine hydrogen (NH) of another amino acid that is
▪ Genetic code also determines protein’s structure and situated four residues ahead in the sequence with 3.6
function residues every turn
▪ Mutation = change of amino acid in a polypeptide chain → Amino acids that favor alpha helix formation:
can cause changes in structure and function of the protein ▪ Alanine
▪ Aspartic acid
▪ Glutamic acid
▪ Leucine

BCHM Amino Acids, Peptides, & Protein Structures 6 of 13

 ▪ Isoleucine
▪ Methionine
→ Amino acids that disrupt alpha helix formation:
▪ Glycine
▪ Proline
→ Examples of structure with alpha helix structure:
▪ Keratin
▪ Collagen
▪ Fibrin
Figure 11. Alpha helix structure of a polypeptide chain
(biochemians.wordpress.com)
2. Beta-Pleated Sheets (β-pleated sheets)
→ Composed of 2 or more different regions stretches of at least
5-10 amino acids (beta strands)
→ Beta strands are extended polypeptide chains
→ Chains are folded so that they lie alongside each other
→ Formed by linking two or more beta strands by interchain
hydrogen bond
→ Pleated due to positioning of the alpha carbons of peptide
bond which alternate above and below the plane of sheet
Figure 12. Beta-pleated sheet structure of polypeptide chains
(http://www231.pair.com)
• Two types:
→ Parallel
▪ Adjacent peptide chains proceed in same direction
▪ Direction of N-terminal and C-terminal ends is the same
→ Anti-parallel
▪ Adjacent peptide chains proceed in opposite direction
▪ One ends with N-terminal while the other ends with C-
terminal
− Example: fatty acid-binding protein
BCHM Amino Acids, Peptides, & Protein Structures
Figure 13. Structures of the parallel and anti-parallel beta-pleated
sheets (quora.com)
Supersecondary Structure
• Turns and Bends
→ Short segments of amino acids that join 2 units of secondary
structure such as two adjacent strands of an antiparallel beta
sheet
→ Beta turns involve 4 aminoacyl residues
▪ Proline and glycine are present in beta turns
• Loops
→ Regions that contain residues beyond the minimum number
necessary to connect adjacent regions of secondary
structure
• Intermediate between secondary and tertiary structure
• Includes structural motifs such as helix-loop-helix
→ formed by combination of secondary structure elements
(alpha helices, beta sheets, non-regular sequences)
• Loops and bends reside on surface of protein and serve as
readily accessible site (epitopes) for binding of antibodies
Figure 14. Structural motif of helix-loop-helix (oregonstate.edu)
Tertiary Structure
• Complete 3D structure of polypeptide units of a protein
• Spatial relationship of different secondary structures
• Domains
→ Formed from folding of different secondary structures
▪ Incorrect folding may produce an alteration in protein
structure (Prion disease)
→ Compact globular functional unit of a protein
→ Relatively independent region of protein
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• Important features:
→ Interior formed by amino acids with hydrophobic side chains
or R-groups
→ Surface formed by hydrophilic amino acids that interact with
aqueous environment
• Chaperone
→ Assists the accurate folding of the secondary structures
• Bonds
→ Formed due to interaction between the R-groups of amino
acids
1. Hydrophobic bonds (noncovalent bond)
• Interaction between nonpolar hydrophobic side chains
→ Causes nonpolar molecules to adhere to one another
→ Major driving force in protein folding
→ Most important bond in protein conformation
→ Hydrophobicity of certain R groups tend to drive them away
from aqueous environment by hydrophobic R group
2. Electrostatic/Ionic bond (noncovalent bond)
→ Attraction between two opposite charges
→ Repulsion between two like charges
→ Types of charges:
▪ Charge-charge – attraction between oppositely-charged
amino acids
▪ Charge-dipole – interaction of ionized R-groups with
dipole water
▪ Dipole-dipole – interaction of R-groups of amino acids
3. Van der Waals force (noncovalent bond)
→ Weak forces of attraction between polar and nonpolar
molecules
→ Summation of various forms of energy resulting from
momentary random fluctuation in the distribution of electrons
around any atom which give rise to a transient unequal
distribution of electron or an electric dipole
4. Disulfide bond (covalent bond)
→ Covalent bonding between R-groups of cysteine amino
acids
→ Found in extracellular proteins
Figure 15. Tertiary structure with different bonds
(bio.libretexts.org)
Quaternary Structure
• Multiple polypeptide chains assembled into multi-subunit or
oligomeric proteins
• Stabilized and maintained by the same forces that hold tertiary
structures
• Types:
→ Homo-oligomers – with identical subunits
→ Hetero-oligomers – with several distinct subunits
▪ Example: hemoglobin with 2 alpha and 2 beta subunits
BCHM Amino Acids, Peptides, & Protein Structures
Figure 16. Quaternary structure of hemoglobin with subunits
(slideserve.com)
C. PROTEIN FOLDING
• Dynamic and modular; the process is orderly but not rigid
• Cooperative process – once a part of the protein initiates
folding, the rest of the polypeptide chain will also fold
• Two stages:
→ 1st Stage:
▪ Folding of short segments of newly synthesized
polypeptide into secondary structural units
→ 2nd Stage:
▪ Hydrophobic regions aggregate into the interior of the
protein, forming a molten globule
• Molten globule – a partially folded polypeptide in which
modules of secondary structure rearrange until mature
conformation is achieved
• Each element of secondary or supersecondary structure
facilitates proper folding by directing the folding process toward
the native conformation (↓ energy state), and away from
unproductive alternatives
• Proteins fold in order to achieve a form that needs the least
energy and is the most stable
Proteins that assist in folding
• These are used to speed up folding and prevent the formation
of aggregates
→ Disulfide isomerase
▪ Involved in rupture and reformation of disulfide bonds
(most stable bond)
→ Proline-cis, trans-isomerase
▪ Converts peptide bond in the proline from trans to cis,
because there are certain forms of proteins that require
the cis form
▪ Trans peptide bond (preceding a proline) → cis
→ Chaperones
▪ Assist the covalent folding/unfolding;
assembly/disassembly of other structures
▪ Prevents aggregates; uses hydrolyzed ATP
▪ Break down barriers that delay the folding of proteins by
using heat shock proteins (which are synthesized when
temperatures are increased)
− Hsp 70 (70 kDA heat shock proteins) – used during the
early stage of protein folding; binds immediately at
protein ribosomes; prevents pre-mature folding
− Hsp 60 (Chaperonins) – barrel-shaped; used during
the latter stage of protein folding to prevent
aggregation
• Aggregates are toxic, insoluble disorder complexes of
unfolded/partially folded polypeptide, held together by
hydrophobic interactions that delay/hinder protein folding
→ Misfolded proteins with no aggregates should be refolded or
degraded by proteases
→ Misfolded proteins with aggregates are resistant to
proteolytic degradation
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 D. COMPLEX PROTEINS http://oregonstate.edu/instruct/bb450/fall14/lecture/proteinstructureIoutline.ht
ml
These are proteins combined with another macromolecule Quora.com. Structures of the Parallel and Anti-Parallel Beta-Pleated Sheets
→ Glycoproteins [digital image]. Retrieved from https://www.quora.com/Why-are-parallel-beta-
▪ Protein + carbohydrate (covalently conjugated) sheets-less-stable-than-anti-parallel-beta-sheets-in-a-folded-protein-molecule
▪ Present in the surface of RBC; used in blood typing Rodwell, V.W., Bender, D.A., Botham, K.M., Kennelly, P.J., & Weil, P.A. (2018).
Harper’s Illustrated Biochemistry. 31e. New York: McGraw-Hill
→ Lipoproteins Education
▪ Proteins associated with lipids Rodwell, V.W., Bender, D.A., Botham, K.M., Kennelly, P.J., Weil, P.A. (2015).
▪ Aids in storage and transport of other lipids Slideserve.com. Quaternary Structure of Hemoglobin with Subunits [digital
▪ LDL, HDL image]. Retrieved from https://www.slideserve.com/ciqala/chapter-20-amino-acids-
• and-proteins
VI. CLINICAL SIGNIFICANCE wps.prenhall.com. Formation of Peptide Bond [digital image]. Retrieved from
http://wps.prenhall.com/wps/media/objects/3085/3159329/blb2507/25
• Collagen – most abundant structural protein -26a.jpg
- Alterations of collagen due to abnormal genes and www231.pair.com. Beta-Pleated Sheet Structure of Polypeptide Chains [digital
image]. Retrieved from
abnormal processing results result in following disorders: http://www231.pair.com/fzwester/courses/bis10v/week2/12proteins.html
Ehlers-Danlos Syndrome, Osteogenic imperfecta,
Marfan’s Syndrome
o Ehlers – Danlos Syndrome – hyperflexibility of
the body
o Osteogenic imperfecta – brittle bones; due to a
defect in collagen synthesis
o Marfan’s Syndrome – fingers and body parts
unusually longer (arachnodactyly)
• Familial Hypercholesterolemia – due to genetic defect in
gene encoding the receptor for LDL
• Carcinogenesis – basic structure of protein is disrupted by
mutation in their genes
• Alzheimer’s Disease – refolding or misfolding of another
protein endogenous to human brain tissue, β-amyloid
• Beta-Thalassemias – genetic defects that impair the
synthesis of one of the polypeptide subunits of hemoglobin;
absence of chaperone, α-hemoglobin stabilizing protein
(AHSP)
• Prions – fatal neurodegenerative disease due to the
deposition of insoluble protein aggregates in neural cells; α-
helices are converted into β-pleated sheets

VIII. REFERENCES
Bio.libretexts.org. Levels of Protein Structure Organization [digital image].
Retrieved from
bio.libretexts.org/Courses/University_of_California_Davis/BIS_2A%3
A_Introductory_Biology_(Facciotti)_MASTER_RESOURCES/Proteins
*%23
Bio.libretexts.org. Tertiary Structure with Different Bonds [digital image].
Retrieved from
https://bio.libretexts.org/Bookshelves/Introductory_and_General_Biology/
Book%3A_General_Biology_(Boundless)/3%3A_Biological_Macromolecules
/3.3%3A_Proteins/3.3C%3A_Protein_Structure
biochemians.wordpress.com. Alpha Helix Structure of a Polypeptide Chain
[digital image]. Retrieved from
https://biochemians.wordpress.com/page/2/
Desertbruchid.net. Secondary Structure (Alpha Helix) with Hydrogen Bonds
[digital image]. Retrieved from
http://desertbruchid.net/4_GB1_LearnRes_fa10_f/4_GB1_LearnRes_
Web_Ch03.html
Ferraro, A. (Photographer). (2014). Liberty enlightening the world [digital image].
Retrieved from https://www.flickr.com/photos/afer92/ 14278571753/in/set-
7215764461703061
geek.doctor/biochemistry (Fig 2)
geek.doctor/biochemistry (Fig 2)
Harper’s Illustrated Biochemistry (30th ed). New York: The McGraw-Hill
Education
Images.tutorvista.com. Structure of a Polypeptide Chain [digital image].
Retrieved from
http://images.tutorvista.com/cms/images/101/polypeptide-chain.png
Mark, A., C, Smith, M. Lierberman. (2005). Basic Medical Biochemistry: A
Clinical Approach (2nd ed). United States of America: Lippincott Williams &
Wilkins, Philadelphia.
Mark, A., C, Smith, M. Lierberman. (2005). Basic Medical Biochemistry: A
Clinical Approach (2nd ed). United States of America: Lippincott Williams &
Wilkins, Philadelphia.
Oregonstate.edu. Structural Motif of Helix-Loop-Helix [digital image]. Retrieved
from

BCHM Amino Acids, Peptides, & Protein Structures 9 of 13

 BIOCHEMISTRY 08/20/2019

Amino Acids, Peptides & Protein Structures Shifting 01

Trans 02
[SUBJECT]
Dr. Phylis C. Rio
[Name
Side Chain of Lecturer] Structure Nutritional
Classification Amino Acid R-group Chemical Structure Classification Requirement

[SUBJECT]
Proline
Pro pyrrolidine imine non-essential
P
[Name of Lecturer]
Non-polar
[SUBJECT]
[Name of Lecturer]
Glycine
Gly -H aliphatic non-essential
G (simple)

Alanine
Ala -CH3 (methyl) aliphatic non-essential
A (simple)

Valine
Val isopropyl aliphatic essential
V (branched)

Leucine
Leu isobutyl aliphatic essential
L (branched)

Isoleucine
Ile sec-butyl aliphatic essential
I (branched)

Methionine
Met thioether aliphatic (sulfur- essential
M containing)

Phenylalanine
Phe benzyl aromatic essential
F

BCHM Espino, Halili, Necosia, Valad-on 1 of 13

 Trytophan
Trp indole aromatic essential
W

Tyrosine
Tyr phenol aromatic non-essential
Polar Y
unionized

Threonine
Thr secondary aliphatic essential
T alcohol (hydroxylic)

Serine
Ser primary alcohol aliphatic non-essential
S (hydroxylic)

Cysteine
Cys primary thiol aliphatic (sulfur- non-essential
C containing)

Glutamine
Gln amide aliphatic non-essential
Q (carboxamide)

Asparagine
Asn amide aliphatic non-essential
N (carboxamide)

Polar Glutamic acid aliphatic

charged Glu carboxyl (monoamino non-essential
negative E dicarboxyl)
(acidic)

Aspartic acid aliphatic

Asp carboxyl (monoamino non-essential
D dicarboxyl)

BCHM Amino Acids, Peptides, & Protein Structures 2 of 13

 Lysine
Polar Lys amino aliphatic essential
charged K (diamino
positive monocarboxyl)
(basic)

Arginine
Arg guanidinium aliphatic semi-essential
R (diamino
monocarboxyl)

Histidine
His imidazole aromatic semi-essential
H (diamino
monocarboxyl)

BCHM Amino Acids, Peptides, & Protein Structures 3 of 13

 A. THE IONIZATION OF LYSINE

B. THE IONIZATION OF HISTIDINE

C. PKA VALUES OF COMMON AMINO ACIDS

BCHM Amino Acids, Peptides, & Protein Structures 4 of 13