Protein folding

The tertiary structure of more than 100,000 proteins^[1] are now known and well characterised. However, the process by which an amino acid chain folds into its native conformation is currently poorly understood. It is a widely held hypothesis^[2] that the native state of a protein is the conformation that has the lowest energy i.e. is the most thermodynamically stable. This suggests that the only determinant of three-dimensional shape is the amino acid chain itself. This is evidenced by the spontaneous reforming of tertiary structure after a protein has been denatured. While the primary structure of a protein can be determined from gene sequencing and the tertiary structures of many proteins have been determined via X-ray crystallography or NMR, the exact mechanism by which the primary structure folds into the tertiary structure is currently unknown. Random sampling of all possible conformations would take an astronomical amount of time—even for sampling on a picosecond time scale—and protein folding takes place in seconds or less.^[2:1]

Determining the detailed mechanism(s) of protein folding is therefore at the forefront of protein research, protein folding having become a field of research in and of itself.^[3] Solving “the protein folding problem” would essentially allow prediction of native state conformation from the gene that^[4] encodes the protein. There are a number of theories as to how protein folding takes place but it is now generally accepted that the folding process involves funnel-shaped energy landscapes; random thermal motions lead to conformational changes that move the protein energetically downhill towards the native structure.^[3:1][5] This view of protein folding means that there are a large number of high-energy, unfolded structures and only a few low-energy folded structures and that the dynamics of both unfolded and natively folded proteins are of critical importance. A number of factors appear to contribute to driving the protein towards its folded state,^[3:2] including hydrogen bonds, van der Waals
and electrostatic interactions, backbone angle preferences and hydrophobic interactions where hydrophobic residues forms a nucleus around which the rest of the secondary structure can develop. This “hydrophobic effect” is a non-specific attraction between the (non-polar) hydrophobic residues. It differs from other “elementary” forces (such as van der Waals) in that it is completely dependant on environment.

Also considered important are the formation of disulfide bridges, and it is possible that early formation of the secondary structure elements may drive the protein towards its native confirmation. Other proteins reach their native state with the assistance of chaperone proteins, but this is mostly a catalytic process and all the information necessary to deduce the final form lies within the amino acid sequence. Uncovering the dynamical processes that lead to the formation of protein tertiary structure could also help to unlock potential treatments for a number of diseases which arise as a result of aggregation of proteins that have misfolded such as prion diseases like Creutzfeldt-Jakob disease. Determining at which step of the pathway the misfold occurs could lead to new treatments for these diseases, and potentially even allow for the development of preventatives