Protein Structure and Folding

More complicated proteins often have more multimers than dimers and more subunits.
Subunits are held together by the same interactions as tertiary structure, not exclusively disulfide bonds.

Proteins fold into specific structures to function.
Proteins can have various structures: long alpha helix (collagen), globular, or seemingly unstructured.

Proposed by Leventhal to understand how proteins fold.
Consider a small protein with 100 amino acids, each with three possible structures.
There are $3^{100}$ possible structures for the protein to fold into.
Even if the protein tries out structures at a rate of $10^{13}$ per second, it would take longer than the age of the universe to sample all possibilities.
Proteins fold correctly in milliseconds or seconds.

Proteins fold through an energy landscape.
Unfolded protein: high potential energy.
Correctly folded protein: lowest potential energy.
Protein folding is like a ball rolling down a landscape; it follows a path to lower energy and doesn't randomly go uphill.
As the protein rolls down the landscape, it doesn't need to try every confirmation.
The protein shifts structures sometimes to try out a different structure, gaining potential energy and moving up the landscape, the proteins eventually reverts back to its stable form.

Anfinsen investigated whether the primary sequence (amino acid sequence) directs protein folding.
He broke up tertiary interactions (e.g., disulfide bridges) to create a primary structure.
The protein refolded into its original state when placed in water, even without chaperones or enzymes.
Conclusion: the primary structure of a protein directs its folding.
Enzymes and chaperones speed up folding, allowing proteins to be functional within a reasonable time frame.

Chaperones assist in protein folding and speed up the process.
They help proteins revert to their original structure faster when they shift structures.
Chaperones can correct misfolded proteins, helping them achieve the correct structure for activity.

Protein structures are sensitive to environmental changes; denaturation occurs when bonds break, and the protein unfolds.
Denaturation conditions:
- Heat: Breaks tertiary structure interactions.
- Non-optimal pH: Protonation or loss of protons disrupts structure. Optimal pH does not necessarily mean neutral (e.g., pepsin in the stomach).
- Too many ions: Ions interfere with ionic bonds (salt bridges), causing the protein to fall apart.
- Too many ions can stem from underhydration.
Maintaining homeostasis is crucial to prevent protein denaturation.

Prions are misfolded proteins that can cause other proteins to misfold, propagating misfolding.
They contribute to neurodegenerative diseases because misfolded proteins accumulate in the brain.
Misfolded prions take up space and cause functional proteins to become nonfunctional.
Example: Creutzfeldt-Jakob disease; scans show lit-up areas in the brain where prions have accumulated, taking the place of functional proteins.

Primary structure: Chain of amino acids connected by peptide bonds.
Secondary structure: Interactions between amino acid backbones (not R groups) through hydrogen bonding, creating alpha helices and beta sheets.

Hydrogen bonds form between amino acid $i$ and amino acid $i + 4$ .
Helices have directionality: right-handed (more common in biology) and left-handed.
The R groups face outwards and are available for tertiary or quaternary structure interactions.

Parallel beta sheets: Amino acid chains run in the same direction (N-terminus to C-terminus).
Antiparallel beta sheets: Amino acid chains run in opposite directions.
Beta turns: Four amino acids create a 180-degree turn in antiparallel strands; glycine and proline are common in beta turns.

Recognizable folding patterns (combinations of alpha helices and beta sheets).
Examples:
- Beta-alpha-beta loop: Beta sheet connected to an alpha helix, connected to another beta sheet (forms a loop).
- Beta barrel: Beta sheets crisscross, forming a hollow barrel shape.
Secondary structure has rigid rules.
All alpha helices have the same structure, with every $i$ amino acid hydrogen bonding with the $i + 4$ amino acid.
Parallel and antiparallel sheets are constant in structure.
Secondary structure involves interactions between the backbone, making it constant compared to tertiary structure, where R group interactions lead to diverse structures. Thus, all backbones are the same and that leads to a constant secondary structure.