BioNome Incorporating 3D – Protein Folding and Modelling

Protein folding is the process by which a polypeptide chain folds into its three-dimensional structure to form a biologically active protein. The structure of a protein is important for its functioning. Folded proteins are held together by various intermolecular interactions. During translation, each protein assembles into a linear chain of amino acids or a random coil with no fixed three-dimensional structure. The amino acids in the chain eventually interact with each other to form a well-defined protein folding. The synthesis of the proper three-dimensional (3D) structure of a protein is determined by its amino acid sequence. The folding of proteins into the right natural conformation is crucial for their functioning. Inactive or toxic proteins that are not properly assembled can malfunction and cause many diseases.

  1. Why Is Protein Folding Important?

The final determination of the three-dimensional structure of a protein has biological significance. The final structure of a protein reveals many channels, receptors, and binding sites and influences how it interacts with other proteins and molecules. Advances in understanding protein folding lead to better analysis of innumerable molecular structures and processes. When proteins fold properly, their function continues unhindered. However, folding errors can occur due to a mutation of one of the primary amino acids in the structure or some other random error. Unfortunately, when coagulation does not occur properly, the changes that occur can cause a variety of diseases and syndromes. A decrease in the amount of properly folded protein in the body leads to a lack of work to perform its function.Unfolded chain and conformational space

The primary structure refers to the linear sequence of amino acid residues in a polypeptide chain.

2. Folding intermediates

Folding intermediates play an important role in determining protein folding and assembly pathways, as well as unfolding and aggregation. However, due to their instability, they are lower than high-resolution techniques.

3. Driving forces of folding

Folding is a spontaneous process driven primarily by hydrophobic interactions, the formation of intramolecular hydrogen bonds, van der Waals forces, and counteracted by conformational entropy. The folding process often begins co-translationally, so that the N-terminus of the protein begins to fold while the C-terminus of the protein is still being synthesized by the ribosome; however, a protein molecule can spontaneously fold during or after biosynthesis.

I) Hydrophobic Effect: For a cell to respond spontaneously, protein folding must be thermodynamically favorable. Because protein folding can be a spontaneous reaction, it should involve negative Gibbs free energy. Reducing the number of hydrophobic side chains exposed to water is a key driver of the folding process. The hydrophobic effect is a phenomenon in which the hydrophobic chains of a protein collapse in the core of the protein (away from the hydrophilic environment). Because van der Waals forces (especially London scattering forces) are very dense, the interaction of several hydrophobic groups in the core of a globular folded protein greatly contributes to the stability of the protein after folding.

4. Models for protein folding

I) Framework model: It is believed that folding begins with the formation of the secondary structure independently of the tertiary structure. and then connect to the closely packed native tertiary structure, or at least before the third system is blocked.

II) Hydrophobic collapse model: It is believed that the first event of the reaction is a relatively uniform decomposition of protein molecules due to hydrophobic effects.

III) Nucleation-condensation mechanism: The initial nucleation of diffuse protein folding promotes further folding. The core consists mostly of a number of adjacent remains with some significant secondary structure interactions.

5. Misfolding

If a protein does not conform to its natural state, it is considered unfolded. This may be due to mutations in the amino acid sequence or disruption of the normal folding process by external factors. An unfolded protein usually consists of β-sheets arranged in a supramolecular structure called a β-crossover structure. These β-leaf-enriched complexes are highly stable, highly insoluble, and generally resistant to proteolysis. Misfolding of proteins can cause unfolding and aggregation of other proteins. An increase in the level of accumulated proteins in the cell leads to the formation of amyloid-like structures that can cause degenerative disorders and cell death. Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Cystic fibrosis, and Gaucher’s disease are occurred due to misfolding in protein.

6. Unfolding

Misfolding of proteins can cause unfolding and aggregation of other proteins. An increase in the level of accumulated proteins in the cell leads to the formation of amyloid-like structures that can cause degenerative disorders and cell death. As a result of weak chemical bonds and disordered interactions, the protein loses its original shape and thus becomes biologically inactive. When a protein is denatured or breaks down, it loses its function. For ex: a change in pH, reagents such as urea and guanidine hydrochloride, and Detergents such as sodium dodecyl sulfate denature proteins by associating with a non-polar group of proteins these factors are responsible for denaturation.

7. Helpers of folding (chaperones)

Molecular chaperones are a class of proteins that help the proper folding of other proteins in the body. All cell sections contain chaperones and interact with the polypeptide chain to form the native three-dimensional form of the protein. However, chaperones are not integrated into the final structure of the protein they support. Chaperons may assist in folding even when the nascent polypeptide is being synthesized by the ribosome and they assist in the de novo folding of proteins or they are repair machines for misfolded protein. In eukaryotic organism chaperones are known as heat shock protein for ex: the Hsp70 protein bind to newly synthesized polypeptide and prevents premature folding.