Protein Folding: Basics, Driving Forces, Experimental Techniques, Challenges & Applications

Protein folding is the process by which a linear chain of amino acids folds into its three-dimensional structure. The folded structure is known as the native state, and it is essential for the protein to function properly.
Importance in Biology
Proteins are the workhorses of the cell. They perform a wide range of functions, including catalyzing biochemical reactions, transporting molecules, and providing structural support.
The three-dimensional structure of a protein determines its function. For example, the enzyme amylase has a cleft that is perfectly shaped to bind to starch molecules. When starch molecules bind to the cleft, amylase can break them down into glucose molecules. If the amylase protein were to misfold, its cleft would no longer be the correct shape, and it would not be able to bind to starch molecules and function properly.
Protein misfolding can lead to a number of diseases, including Alzheimer's disease, Parkinson's disease, and cystic fibrosis. In these diseases, proteins fold incorrectly and form aggregates that can damage cells and tissues.

Proteins have four levels of structure: primary, secondary, tertiary, and quaternary.
The primary structure of a protein is its amino acid sequence.
The secondary structure of a protein is the local arrangement of amino acids in the polypeptide chain. The two most common types of secondary structure are alpha helices and beta sheets.
The tertiary structure of a protein is the three-dimensional arrangement of secondary structures. The tertiary structure is determined by the interactions between the amino acids in the polypeptide chain.
The quaternary structure of a protein is the interaction between multiple polypeptide chains. Some proteins are made up of a single polypeptide chain, while others are made up of multiple polypeptide chains.


The energy landscape of a protein is a graph that shows the energy of the protein at different conformations. The native state of the protein is the lowest energy conformation, or the global minimum. However, there are many other local minima on the energy landscape. These are conformations that are lower in energy than the unfolded state, but they are not the lowest energy conformation.

The native state of a protein is the most stable conformation of the protein. It is the conformation with the lowest energy. The unfolded state of a protein is the least stable conformation of the protein. It is the conformation with the highest energy.

Anfinsen's thermodynamic hypothesis states that the native state of a protein is the most stable conformation of the protein. This means that the native state is the conformation with the lowest energy.

Levinthal's paradox
Levinthal calculated that it would take a protein trillions of years to fold into its native state by randomly sampling all possible conformations. However, proteins fold into their native states in milliseconds to seconds.

Protein Folding Experimental techniques:
Circular Dichroism (CD)
X-ray Crystallography
Nuclear Magnetic Resonance (NMR) spectroscopy
Mass Spectrometry
Fluorescence Spectroscopy
Cryo-Electron Microscopy

Protein Folding Computational Methods
Molecular Dynamics Simulation
Monte Carlo Simulation
Rosetta
FoldIt (crowdsourcing)
Deep learning approaches (e.g., AlphaFold)



00:00 Title
00:05 Topics Covered
00:20 Introduction
01:27 Protein Structure Hierarchy
02:08 Forces Driving Protein Folding
03:26 Protein Folding Pathways
04:12 Protein Folding Problems
05:20 Experimental Techniques
06:52 Computational Tools for Protein Folding
08:09 Protein Stability
08:51 Challenges in Protein Folding studies
09:47 Recent Advances in Protein Folding Research
10:15 Conclusion

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