The Three Dimensional Structure of Proteins

Native state

The most stable 3D structure of a protein, which has the lowest energy and maximum entropy

Confirmation vs configuration

Confirmation: Shape due to ROTATION and SINGLE BONDS

Configuration: Fixed arrangement by breaking bonds

Why is the 3D structure essential for function?

A protein must fold into its native CONFORMATION to become biologically active. It allows it to interact with other molecules.

Secondary structure bond

Hydrogen bonds between the carbonyl oxygen and the amido hydrogen of the peptide bond

Right-handed alpha helix is stabilized by

Stabilized by H-bonds, four residues ahead

What disrupts the formation of a right-handed helix (3)

Proline - Kinks

Glycine - Too flexible

Adjacent bulky or like-charged side chains (steric/ electrostatic hindrance)

Helix capping

Folding of the polypeptide chain to provide H-bond partners for the unpaired groups at the helix ends, stabilizing the helix

What stabilizes beta sheets?

Stabilized by H-bonds between neighboring strands

Parallel beta sheets vs antiparallel beta sheets

Parallel - Require more strands for stability. Strands run in the same direction.

Antiparallel - More stable due to optimal H-bond geometry. Strands run in the opposite direction.

What is a beta-bulge?

Distortion in an antiparallel beta sheet where one strand has extra residue, causing a slight bend

What is a beta turn?

180-degree reversal in the peptide chain over 4 amino acids long

What stabilized a beta turn?

Stabilized by an H-bond between residues 1 and 4

Type I vs Type II beta turns

Type I - Proline at position 2

Type II - Glycine at position 3 and no proline

How are secondary structures maintained

H-bond between the carbonyl oxygen and amido hydrogen of the peptide backbone maintains secondary structures

What stabilizes tertiary structures? (2)(5)

Intramolecular forces that stabilize tertiary structures:

1. Hydrophobic interactions (nonpolar side chains)

2. Hydrogen bonds (Polar or charged side chains)

3. Salt bridges (electrostatic interactions)

4. Hydration

5. Disulfide bonds

Same for quaternary structures

Structural motifs vs domains

Structural motif - Small, common combinations of secondary structures. Not stable independently. (EX: Beta barrel)

Domains - Independently folded, compact units within a protein that have specific biochemical functions. Stable independently.

Non-regular, non-repeating structures vs Intrinsically unstructured/ natively unfolded proteins

Non-regular, non-repeating structures - Segments of polypeptide chains that lack a regular alpha helix or beta sheet secondary structure. Loops or coils that connect structural elements.

Intrinsically unstructured/ natively unfolded proteins - Proteins or protein regions that do not have a defined 3D structure but are functional. Become more structured upon binding to other molecules.

Why is entropy unfavorable during protein folding?

Folding reduces conformational freedom (entropy) of the polypeptide chain. Entropy prefers a random coil vs a structured state.

Enthalpic changes that favor protein folding (2)(3)

Intramolecular side chain interactions:

1. Hydrogen bonds

2. Ionic interactions

3. Van der Waals forces

Stabilize the folded state, lowering the enthalpy

Hydrophobic effect

Hydrophobic side chains bury in the protein core, releasing structured water and increasing the entropy of the surrounding SOLVENT, which favors folding

Chaperones vs chaperonins

Chaperones - Proteins that assist the folding of other proteins by preventing misfolding and aggregation

Chaperonins - Subclass of chaperones that provide an isolated environment for proteins to fold correctly, often barrel-shaped

Fibrous proteins vs Globular proteins and examples

Fibrous proteins - Long, insoluble proteins with structural roles. Often composed of repeating sequences and dominated by secondary structures.

EX: Collagen and keratin

Globular proteins - Compact, soluble proteins with diverse functions. Containing mixed secondary and tertiary structures

EX: Enzymes and antibodies

Prosthetic group examples (4)

Metals

Heme

Lipids

Carbs (O-linked and N-linked)

Denaturation vs hydrolysis

Denaturation - Disruption of structures (except primary) WITHOUT breaking peptide bonds, causing loss of function.

Hydrolysis - Breaks peptide bonds, affecting primary structure.

Collagen primary structure

Repeating -Gly-Pro-X- or -Hyp-Gly-X where X is often lysine

Hyp is 4-hydroxyproline

Collagen secondary structure name, composition, and what happens?

Protopocollagen polypeptide

Contains terminal globular domains on both ends and a LEFT-handed helix

Transported to the smooth ER, where it adds a hydroxyl group to proline and lysine. Requires Vitamin C (Ascorbic acid)

Collagen tertiary structure name, composition, and what happens?

Tropocollagen

Triple helical structure starting at the carboxyl terminal to the amino terminal.

Heat shock protein is needed.

“Quaternary” structure of collagen name, composition, and what happens?

Collagen

Enzymes cleave off the domains to make collagen

Self-associate into a staggered overlapping arrangement

Hydrophobic interactions hold the helix together

Prion disease structural change

Prion protein transitions from having few beta sheet structures to having a lot.

Prion disease consequences (2)

Resistant to denaturation and proteolysis because of the high beta-sheet structure, making them stable.

Neurodegenerative disorder due to protein aggregation and cell death

How does an abnormal prion effect normal proteins?

Effect normal proteins by binding to them and inducing them to refold to an abnormal, beta-rich form