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50+ year old protein paradox solved

Proteins make life possible. They are the products made from all of our DNA programming. Now, researchers can accurately predict how changes in protein volume changes their folding and unfolding — making them more or less affective. As proteins may even be evolving below oceans on ice-bound exo-planets orbiting stars that are not our Sun, knowing how proteins work is not only critical for life as we live now, but might also impact our future in space.

Proteins must stay folded to perform their functions when under the immense pressures in the depth of oceans. Yet other proteins unfold under pressure and are inoperable. How can these differences co-exist?

It may depend on the volume of the protein in question. Research published in Nature Communications states it is possible to predict how the volume of a given protein will change between its folded and unfolded states. Mathematical computations can now accurately predict how a protein will react under pressure. Such information also sheds light on inner-workings of life at earth's ocean depths — and may eventually give us insights into how alien life on other planets exists.

"We're finding planets with oceans that, although cold on the surface, are likely warm at the bottom. So what would life look like in that environment?

"With this computational ability, we can look at the proteome of barophillic organisms [organisms which thrive at high pressures] on Earth and ask — how do their proteins adapt?"

George Makhatadze PhD, Constellation Professor, Biocomputation and Bioinformatics, member The Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York, USA

Scientists have long known that a protein will unfold under increased pressure — if its unfolded state has a lower volume — but, will remain folded if the unfolded state has a higher volume.

The protein volume paradox dates back to the first X-ray pictures of proteins. Images showed 30% of a protein's volume is made up of the voids and cavities of an imperfectly packed structure of atoms.

But, while scientists experimentally measured a range of -4% to +1% change in volume as proteins immersed in water go from folded to unfolded, computations predicting those measurements were rare.

Researchers assumed proteins would lose about 30 percent of their volume when unfolded, yet could not explain the difference between that figure and experimental results.

So they hypothesized that unfolded proteins interacted with water in which they were immersed and increased in volume. They proposed a "transfer method" to calculate the effect of losing water volume. However, that method yielded only a small decrease in volume, increasing the imbalance between all measurements.

Makhatadze's group found 2 mistaken assumptions in theories about the paradox.

• Although atoms in an unfolded protein are less densely packed than a folded one, a complex shape always retains some voids and cavities, so a 30 percent decrease in volume is unrealistic.

• Also, the transfer method begins with an error: that a non-aqueous solvent creates a volume-boosting buffer which disappears if compounds are immersed in water.

The research group wrote a computer program that accurately calculated the volume of an unfolded protein — published separately in a 2015 edition of BMC Bioinformatics — finding a 7% 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.

"So these two factors — volume change when voids and cavities are eliminated through unfolding, and volume change as the unfolded protein is exposed to water — are cancelling each other out in a very intricate way."

George Makhatadze PhD

Then Makhatadze's group went a step further, finding a common property in the volume change of 140 molecules. When model compounds were immersed in water, certain areas of those molecules increased in volume, namely non-polar areas — or those areas that do not interact with water.

With that information, the group calculated the percentage change in volume for more than 200 proteins and matched the observed range of -4% to +1%.

"Not only do we reach the experimental range, we can also quantitatively predict the volume changes for a given protein."

George Makhatadze PhD

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Hydrostatic pressure is an important environmental variable that plays an essential role in biological adaptation for many extremophilic organisms (for example, piezophiles). Increase in hydrostatic pressure, much like increase in temperature, perturbs the thermodynamic equilibrium between native and unfolded states of proteins. Experimentally, it has been observed that increase in hydrostatic pressure can both increase and decrease protein stability. These observations suggest that volume changes upon protein unfolding can be both positive and negative. The molecular details of this difference in sign of volume changes have been puzzling the field for the past 50 years. Here we present a comprehensive thermodynamic model that provides in-depth analysis of the contribution of various molecular determinants to the volume changes upon protein unfolding. Comparison with experimental data shows that the model allows quantitative predictions of volume changes upon protein unfolding, thus paving the way to proteome-wide computational comparison of proteins from different extremophilic organisms.

R. Chen, a graduate student in biological sciences, joined Makhatadze in the research, which was funded by the National Science Foundation Chemistry and Life Processes, and used the resources of the Rensselaer Center for Computational Innovations and the Extreme Science and Engineering Discovery Environment (XSEDE).

Makhatadze's research is enabled by the vision of The New Polytechnic, an emerging paradigm for higher education which recognizes that global challenges and opportunities are so great they cannot be adequately addressed by even the most talented person working alone. Rensselaer serves as a crossroads for collaboration -- working with partners across disciplines, sectors, and geographic regions -- to address complex global challenges, using the most advanced tools and technologies, many of which are developed at Rensselaer. Research at Rensselaer addresses some of the world's most pressing technological challenges -- from energy security and sustainable development to biotechnology and human health. The New Polytechnic is transformative in the global impact of research, in its innovative pedagogy, and in the lives of students at Rensselaer.

About Rensselaer Polytechnic Institute
Rensselaer Polytechnic Institute, founded in 1824, is America's first technological research university. For nearly 200 years, Rensselaer has been defining the scientific and technological advances of our world. Rensselaer faculty and alumni represent 85 members of the National Academy of Engineering, 17 members of the National Academy of Science, 25 members of the American Academy of Arts and Sciences, 8 members of the National Academy of Medicine, 7 members of the National Academy of Inventors, and 4 members of the National Inventors Hall of Fame, as well as a Nobel Prize winner in Physics. With 7,000 students and nearly 100,000 living alumni, Rensselaer is addressing the global challenges facing the 21st century--to change lives, to advance society, and to change the world. To learn more, go to http://www.rpi.edu.

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Mar 3, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   

Volume enclosed by the RED LINE is the geometric — or Volume Solvent-Excluded (VSE) area.
Its molecular surface is then calculated by using solvent probes of 1.4 Å (BLUE SPHERES).
The VSE is now found to consist of van der Waals volume (DARK LINED YELLOW area, VvdW),
a volume occupied by protein atoms, as measured against the void volume (GREY AREAS, VVoid).
Upon protein unfolding, the molecular surface of the protein increases and some of the voids
become solvent exposed.

Image Credit: Stanislav Shvartsman, Department of Chemical and Biological Engineering

Phospholid by Wikipedia