Size is everything: X-ray protein volume

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  • Published: Feb 15, 2017
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Size is everything: X-ray protein volume

Paradoxical proteins

Molecular determinant of the effects of hydrostatic pressure on protein folding stability (Credit: Nature/Makhatadze et al)

Researchers in the US appear to have solved a paradox regarding the changing volume of proteins that dates back half a century. The team can now predict accurately through computational work how volume will change for a given protein between its folded and unfolded state. The study might shed light on the inner workings of life under pressure in the ocean depths and could have implications for understanding alien biochemistry should we ever identify life on other planets.

Some proteins can survive crushing pressures by staying folded yet others unfold when the pressure is on. This seeming protein volume paradox dates back to the first X-ray structures of proteins from about the middle of the twentieth century. Structure showed that 30 percent of the volume of a protein is comprised of voids and cavities inside the imperfectly packed structure and protein crystallographers had assumed that as such, proteins would lose about 30 percent of their volume when unfolded, but this is not always the case. New work by a team in the US offers an explanation.


"We're finding planets with ocean that, although cold at the surface, are likely warm at the bottom. So what would life look like in that space?" explains George Makhatadze of the Center for Biotechnology and Interdisciplinary Studies at Rensselaer Polytechnic Institute, New York. "With this computational ability, we can look at the proteome of barophillic organisms on Earth and ask - how do their proteins adapt?"

It has been known for some time that a protein will unfold under increased pressure if its unfolded state has a lower volume than its folded conformation. Conversely, it will remain folded if the unfolded state has a higher volume. Until now, predictive computation has not matched experimental measurements. However, seeking to resolve the difference, researchers hypothesized that unfolded proteins were interacting with the water in which they were immersed, gaining volume, and proposed a "transfer method" to calculate that effect. Tweaks and fudges never resolved the paradox.

Now, Makhatadze's group have shown that there were several incorrect assumptions being made in considering the protein volume paradox. Although the atoms of an unfolded protein are less densely packed than a folded one, the complex shape retains some voids and cavities, so a 30 percent decrease in volume is unlikely. Also, the transfer method begins in error because the non-aqueous solvent creates a volume-boosting buffer that disappears when compounds are immersed in water. The team's new computer algorithm now accurately calculate the volume of the unfolded protein and finds a 7 percent decrease in volume based on lost voids and cavities. Switching to a transfer method that moves compounds from a gas phase to water produced a slight increase in volume.

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"So these two factors - the volume change when voids and cavities are eliminated through unfolding, and the volume change as the unfolded protein is exposed to water - are cancelling each other out in a very intricate way," Makhatadze explains. Additional work, showed that only hydrophobic regions of the model structures increase in volume when immersed in water. With that additional detail in hand, the team calculated the percentage volume change for more than 200 proteins and matched these to observed ranges of -4% to +1%. "Not only do we reach the experimental range, we can also quantitatively predict the volume changes for a given protein," Makhatadze adds.

Related Links

Nature Commun 2017, online: "Molecular determinant of the effects of hydrostatic pressure on protein folding stability"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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