A molecular simulation demonstrates proteins re-folding at extremely low temperatures

The folding and unfolding of a protein, which heavily depends on the temperature of its surrounding environment, plays a crucial role in many biological functions.

Previously researchers thought that sufficient heating or cooling of proteins would cause them to unfold. However, Kozuch et al. examined the Trp-cage mini-protein in supercooled water and found that although the protein unfolded under moderate supercooling, when the temperature reached below 55 K the protein surprisingly refolded.

“Our results suggest that there exists a previously unknown region of stability at supercooled conditions, far below the freezing point of water, where the folded state of the protein is stabilized, at least over the microsecond time scales that we sampled,” author Daniel Kozuch said.

They believe that the refolding of the protein at such low temperature is driven by the desolvation of the hydrophobic core, which in turn is related to the decrease in density in supercooled water. “Water is critical to protein folding, as energetic and entropic interactions between the protein and water provide much of the driving force for protein folding,” co-author Pablo Debenedetti said.

To ensure accuracy, the authors ran two independent sets of simulations; one with the protein started in the folded state and one with the protein started in the unfolded state. They obtained the same result in both cases.

“This result not only holds significance for current work in low temperature systems, but also has implications for life under extreme conditions,” said co-author Frank Stillinger.

The authors are currently performing the same calculation but with different proteins.

Source: “Low temperature protein refolding suggested by molecular simulation,” by Daniel J. Kozuch, Frank H. Stillinger, and Pablo G. Debenedetti, Journal of Chemical Physics (2019). The article can be accessed at https://doi.org/10.1063/1.5128211 .