Restructuring biology: New study shows protein hydrophobic parts do not hate water

In our cells, proteins are first formed as a chain of compounds called amino acids. Parts of this chain are "hydrophilic," or easily water-soluble. Other parts were to date thought to be "hydrophobic," or water-repelling. This hydrophobicity is what is called into question by the pair of Japanese scientists.

Interactions among the amino acids and between amino acids and water cause the protein to successively fold in on itself. The folding patterns are pre-programmed for each protein, and the folded structures are designed to enable specific interactions with other molecules for specific functions. In other words, proteins must transition from an unfolded state to a folded one to function properly; the misfolding of proteins can lead to a wide variety of diseases, such as Alzheimer's, cystic fibrosis, or even allergies.

In 1959, a theory was proposed of the mechanism behind protein folding. This classical theory posits that hating water, i.e., the exposure of the hydrophobic parts to water, is energetically unfavorable, and thus causes the proteins to always fold in a manner that tucks away the hydrophobic parts into the interior of the protein structure. This means that the hydrophobic repulsive force stabilizes the folded protein structure. Over the decades that followed, many observations proved this theory too broad and simplistic and therefore, it has been refined to include consideration of the force of attraction between the hydrophobic parts (the van der Waals force). However, the hydrophobic repulsion has continued to be considered the force behind the folding.

According to the two Japanese scientists, Dr. Tomonari Sumi (Okayama University) and Dr. Hiroshi Imamura (Ritsumeikan University), this theory seems to ignore another key contribution at play, the cavity formation energy (or energy needed to form a space to accommodate the buried parts into protein interior).

To reveal the contribution of all these interactions on the protein folding stability, the scientists conducted theoretical calculations using a new computational method called the reference-modified density functional theory. For their calculations, they used a typical model for hydrophobic interactions, the coiled-coil protein GCN4-p1, which folds into a two-layered structure called the leucine zipper (because it looks like a closed zipper). The scientists studied the energies required for the folding and unfolding processes.

Their findings were quite the surprise. "Our study shows that when the proteins are unfolded, the interactions of the hydrophobic parts with water (the van der Waals force) actually stabilizes the unfolded structure. So, the classical view of the hydrophobic groups 'hating' water and thus causing the protein to fold is not appropriate," explains Dr. Sumi. "Instead, the fact is that the van der Waals force between the hydrophobic parts is stronger than the 'effective' water-mediated repulsive force between them, and so, the proteins fold over. It is the direct attraction between the molecules rather than the repulsion with water that causes the folding. The intramolecular van der Waals force is the stabilizing force in the folded structure."

The scientists hope that these findings will prompt further investigation into this phenomenon and a re-look at the science the classical theory has informed. They also hope that this percolates down to core education and textbooks change their explanations of the phenomenon.

Dr. Imamura says: "In our results, the 'visible' phenomenon, which is that the proteins fold to stably tuck the hydrophobic groups in the core of the structure, remains the same, but our understanding of the underlying mechanism must change."

The scientists hope that their findings soon become widely accepted and the ripple effects of that are seen in engineering and pharmaceutical applications as well.