Protein Folding

Introduction to protein folding

Protein folding is the process by which a protein chain acquires its native 3-dimensional structure. It is a fundamental aspect of molecular biology, biochemistry, and structural biology. The shape of a protein is important because it determines the function of the protein. If a protein does not fold into the correct shape, it cannot function properly, leading to diseases such as Alzheimer's, Parkinson's, and cystic fibrosis.

Basics of protein structure

Proteins are composed of amino acids linked together in long chains, typically ranging from 50 to 2000 amino acids. The sequence of amino acids is defined by primary structure of the protein and is encoded by the corresponding gene.

Primary structure

The primary structure of a protein is a simple linear sequence of amino acids. It is held together by covalent bonds known as peptide bonds. An example can be represented as follows:

Ala-Gly-Ser-Val-Pro-Leu

In this sequence, each three-letter code represents an amino acid, and the dashes indicate the peptide bonds holding them together.

Secondary structure

Secondary structure refers to local folded structures that form within a polypeptide due to interactions between backbone atoms. The most common secondary structures are the α-helix and the β-sheet.

α-helix: A right-handed helix that results from hydrogen bonds between key atoms, usually every fourth amino acid.
β-sheet: A sheet-like structure consisting of beta strands that are laterally linked by at least two or three backbone hydrogen bonds.

The hydrogen bonding pattern in a β-sheet looks like this:

Tertiary structure

Tertiary structure is the overall 3D structure of a single protein molecule; the spatial relationship of the secondary structures to one another. This level of structure is determined by interactions between the side chains (R groups) of amino acids:

• Hydrophobic interactions
• Hydrogen bonds
• Disulfide bridges
• Van der Waals force

Here's an example of how a polypeptide folds into a typical globular protein:

Quaternary structure

Quaternary structure is a structure formed by several protein molecules (polypeptide chains), commonly called protein subunits, that function as a single protein complex.

Forces that drive protein folding

Protein folding is primarily directed by biochemical interactions:

• Hydrophobic interactions, which collapse the structure to minimize contact with water.
• Hydrogen bonding stabilizes folded proteins by forming bonds between hydrogen and electric dipoles.
• Van der Waals forces, weak attractions between closely spaced atoms.
• Disulfide linkages, covalent bonds that stabilize the folded structure.

Protein folding pathways

Proteins fold through several pathways to reach their functional form. These pathways include a rapid collapse into a molten globular state followed by a slow search to find the native structure. These steps can be summarized as follows:

1. Formation of secondary structure: α-helix and β-sheet
2. Rapid collapse to a denser state: molten sphere
3. Reaching the original state through various intermediate states

Chaperones and protein folding

Molecular chaperones are proteins that help other proteins fold correctly. They help prevent misfolding and aggregation that could lead to potential cell toxicity. Examples include Hsp60s, Hsp70s, and chaperonins.

Protein misfolding and disease

Misfolding or misfolding of proteins can cause diseases. Misfolded proteins can aggregate into toxic forms. Some examples of disorders caused by protein misfolding include:

• Alzheimer's disease: Misfolded amyloid-β peptides aggregate to form plaques.
• Parkinson's disease: Misfolded α-synuclein protein causes aggregation.
• Cystic fibrosis: A single phenylalanine deletion causes misfolding of the CFTR protein.

Thermodynamics and protein folding

Under physiological conditions the folding process is generally thermodynamically favorable. It can be represented by the equation:

ΔG = ΔH – TΔS

where ΔG is the change in Gibbs free energy, ΔH is the change in enthalpy, T is the temperature, and ΔS is the change in entropy. The native folded state of a protein is generally considered to have its lowest Gibbs free energy.

Pioneering research and future directions

Early research on protein folding was led by scientists such as Christian Anfinsen, who believed that all the information needed to fold a protein was contained in its amino acid sequence. His famous experiment with ribonuclease A led to this conclusion, which became the basis for future research.

New computational models such as AlphaFold have revolutionized our ability to predict protein structures with remarkable accuracy, which has the potential to aid in understanding complex diseases and drug discovery.

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