Amino Acids and Protein Structure

What is the roadmap for amino acids in biochemistry?

Side-chain chemistry → molecular interactions → protein folding → protein function

Describe the components of all amino acids

Attached to the alpha carbon is (with the exception of proline):

• A carboxylic group (negative)

• An amino group (positive)

• A hydrogen atom

• A substituent (R side chain)

  • What allows amino acids to behave different from one another

What is a Zwitterion?

It means that an amino acid contains both positive and negative formal charges

What feature allows amino acids to behave differently from one another?

The R group

• Leucine: a hydrocarbon R group

  • Hydrophobic, no interactions

Explain the chemistry of nonpolar R side chains

• Hydrophobic / poorly compatible with water

• Tend to cluster away from water through the hydrophobic effect

Explain the chemistry of polar R side chains

• Uncharged

• Hydrophilic / compatible with water

• Can form hydrogen bonds and/or dipole-dipole interactions with water

Explain the chemistry of negatively charged R side chains

• Strongly hydrophilic

• Highly compatible with water

• Interact strongly with water via ion-dipole interactions and hydrogen bonding

Explain the chemistry of positively charged R side chains

• Strongly hydrophilic

• Highly compatible with water

• Interact strongly with water via ion-dipole interactions and hydrogen bonding

Nonpolar/Hydrophobic Amino Acids

Amino acids that feature hydrocarbon chains that avoid water and form the hydrophobic cores of folded proteins

• Alanine (Ala, A)

• Glycine (Gly, G)

  • Allow for high backbone flexibility

• Isoleucine (Ile, I)

• Leucine (Leu, L)

• Methionine (Met, M)

  • Contains a sulfur

• Valine (Val, V)

Aromatic Hydrophobic Amino Acids

Amino acids that contain bulky ring structures and contribute to hydrophobic interactions

• Phenylalanine (Phe, F)

• Tryptophan (Trp, W)

• Tyrosine (Tyr, Y)

  • Contains a hydroxyl group

Polar Uncharged (Hydrophilic) Amino Acids

Amino acids whose side chains contain oxygen, sulfur, or nitrogen atoms that can form hydrogen bonds with water

• Asparagine (Asn, N)

• Cysteine (Cys, C)

  • Can form covalent disulfide bonds with other cysteines

• Glutamine (Gln, Q)

• Serine (Ser, S)

• Threonine (Thr, T)

• Proline (Pro, P)

Basic (Positively Charged)

Amino acids that have nitrogen-rich groups in their side chains that readily accept protons (carry a net positive charge at physiological pH)

• Arginine (Arg, R)

• Histidine (His, H)

  • Contains an aromatic imidazole ring that can be neutral or positive depending on the local pH

• Lysine (Lys, K)

Acidic (Negatively Charged)

Amino acids that possess extra carboxyl groups in their side chains that can donate protons (leaves them negatively charged at cellular pH)

• Aspartic acid / Aspartate (Asp, D)

• Glutamic acid / Glutamate (Glu, E)

Define hydrophobic interactions

Nonpolar surfaces minimizes unfavorable contact with water

• Noncovalent

Define hydrogen bond interactions

Polar donor/acceptor atoms that share favorable interactions

• Noncovalent

Define ionic attraction/interactions

Opposite charges attract; affected by pH

• Noncovalent

Define aromatic/Van der Waals interactions

Rings and nonpolar surfaces pack favorably

• Noncovalent

Define disulfide bond interactions

Cys-S-S-Cys covalent linkage

• The only covalent interaction out of the five major types

How do IMFs relate to side chain chemistry?

Protein structure and function depend on intermolecular forces which are determined by the chemical structures and properties of amino acid side chains as well as pH

• pH → chemical properties → control interactions with water → drive residue-residue interactions → promote protein folding → shape protein structure and function

Example of predicting consequences of amino acid substitutions

Asp → Val. Loss of charge and H-bonding may result in lower solubility and lower protein stability

• Asp

  • Negatively charged

  • Hydrophilic

  • Can form H-bonds and ionic interactions

• Val

  • Nonpolar

  • Hydrophobic

  • No ionic interactions

What is the roadmap for protein structure in biochemistry?

Amino-acid sequence → side chain chemistry → molecular interactions → protein folding → protein function

How does the hydrophobic effect impact protein folding?

• An unfolded polypeptide is flexible and disordered with both polar and nonpolar side chains exposed to water

• A folded globular protein has a compact, ordered 3D structure

  • Nonpolar side chains are largely buried

  • Polar/charged side chains are largely exposed to water

  • Entropy gain favors protein folding

How does a protein’s 3D structure help enable its function?

The amino acids are positioned close to each other and can interact in order to create cavities that serve as binding sites for a variety of compounds or molecules

What is a peptide backbone?

A strong covalent bond formed between the backbone of a carbonyl carbon of one AA and the backbone nitrogen of the next AA

• Protein structure is simplified by repetition

• Peptide-bond resonance creates partial double-bond character (strong), resulting in restricted rotation

How do pH and pKa determine amino acid charge?

• As pH increases, an amino acid will generally lose H+

  • Would cause the [A-]/[HA] ratio to go up (more base)

• Creates a more negative charge

Describe primary structure

• An unfolded peptide

• Linear chain of amino acids

• Stabilized/linked by covalent peptide bonds

Describe secondary structure

• Local folding

• Stabilized by backbone hydrogen bonds

Describe the makeup of an alpha-helix in secondary structure

The polypeptide backbone C=O of one amino acid will form a hydrogen bond with the backbone N-H after four residues (i + 4)

• C=O …. H-N

Describe the makeup of beta-sheets in secondary structure

• Antiparallel beta-sheets generally have slightly stronger hydrogen bonding compared to parallel sheets because the polypeptide backbone C=O … H-N bonds are more linear

• Gives better alignment between the donor N-H and acceptor C=O groups

  • Makes the interaction more favorable

Describe connectors between secondary structural elements

The frequency of secondary structure elements is the reason globular proteins are globular

• Essentially how the protein folds into a compact, roughly spherical, or ball-like shape

• The backbone C=O of residue 1 to the N-H of reside 4 helps stabilize tight turns

Describe tertiary structure

• Folded peptide (monomeric)

• Stabilized by hydrophobic effect, hydrogen bonds, ionic interactions, van der Waals, and disulfide bonds

Describe quaternary structure

• At least two folded peptides together

  • Dimer (2), trimer (3), tetrameter (4), etc.

• Stabilized by noncovalent interactions between subunits

  • Can sometimes be disulfide bonds