Life in a Drop: Ohio Supercomputer Helps Prove Hydration’s Role in Protein Folding

By John Russell

July 14, 2016

It’s perhaps fitting that in the middle of the summer, when water management is a common challenge, that a paper in the Proceeding of the National Academy of Sciences (PNAS) offers more proof that life as we know it can’t occur without water. Using Ohio Supercomputing Center resources, researchers have shown the critical role water plays in actively guiding protein folding and movement.

“For a long time, scientists have been trying to figure out how water interacts with proteins. This is a fundamental problem that relates to protein structure, stability, dynamics and—finally—function,” said Dongping Zhong, Robert Smith Professor of physics at Ohio State and leader of the Ohio State University research team that made the discovery. “We believe we now have strong direct evidence that on ultrafast time scales (picoseconds, or trillionths of a second), water modulates protein fluctuations.”

The study is a significant step forward in the understanding of water-protein interactions and answers a question that’s been dogging research into protein dynamics for decades – whether proteins can fold themselves. The answer seems to be they can’t.

The group’s work is reported online (Dynamics and mechanism of ultrafast water– protein interactions) ahead of PNAS publication. Proteins are key actors in virtually all physiological processes and are also key components of many tissues (hair and skin for example). They are typically very large macromolecules (on average around 34 kilodaltons) whose ability to function properly depends upon folding correctly. It turns out water does most of the work.

The researchers note a recently proposed a model for protein dynamics in which large-scale protein motions are controlled by fluctuations of bulk solvent and controlled by solvent viscosity but that internal protein motions – including folding – a controlled by the fluctuations of the hydration (water molecule) shell.

“However, direct measurements of such coupled fluctuations at physiological temperature are challenging as a result of the ultrafast nature of water motions, and therefore most studies are indirect or at low temperature. Here, we used a tryptophan (W) scan to probe global surface hydration and used femtosecond spectroscopy to follow hydration water motions and local side-chain fluctuations in real time. With temperature dependence, we systematically measured their dynamics and thus finally elucidate their ultimate relationship,” write Zhong and his colleagues.

Molecular dynamics simulations performed on OSC resources were instrumental in helping the researchers visualize protein-water interactions: where the water moved a certain way, the protein folded nanoseconds later, as if the water molecules were nudging the protein into shape. The work was performed on both the HP/Intel Xeon Oakley Cluster and recently retired IBM 1350/AMD Glenn Cluster at OSC.

Total water molecules within 10 Å to the tryptophan indole ring, separated 5 Å (red) and 5–10 Å (blue) to the protein surface from the buried, to partially buried, and finally to exposed positions from a snapshot of MD simulations.
Total water molecules within 10 Å to the tryptophan indole ring, separated 5 Å (red) and 5–10 Å (blue) to the protein surface from the buried, to partially buried, and finally to exposed positions from a snapshot of MD simulations.

“With computer simulation, we can identify which water molecules contribute the most to the protein fluctuations, and how they move in space and time,” noted, Yangzhong Qin, a post-doc and author who led the simulation efforts. “The new machine has faster speed than the old cluster, which significantly reduces our simulation time. We used to break the simulation into multiple parts due to the simulation time limit, but now we only need to break it into a few parts or no breaking. This saves us a lot of efforts in the later-stage data processing. Also, with the faster speed, we can push the simulation to longer time scale, which is always better for obtaining more complete and reliable simulation result.”

The Oakley Cluster features more cores on half as many nodes (694) as the center’s former flagship system. Here’s a snapshot of Oakley system specifications:

  • 8,328 total cores – 12 cores/node and 48 gigabytes of memory/node
  • Intel Xeon x5650 CPUs
  • HP SL390 G7 Nodes
  • 128 NVIDIA Tesla M2070 GPUs
  • QDR IB Interconnect with low latency; high throughput; and high quality-of-service.
  • Theoretical system peak performance of more than 88 teraflops, which when combined with GPU acceleration (additional 66 teraflops), rises to peak performance of 154 teraflops
  • Memory increase from 2.5 gigabytes per core to 4.0 gigabytes per core.
  • Storage expansion of 600 terabytes of DataDirect Networks Lustre storage for a total of nearly two petabytes of available disk storage.
  • System efficiency is 1.5x the performance of current systems at just 60 percent of current power consumption.

Researchers did not make use of Oakley’s GPU acceleration, according to Qin. The familiar AMBER software package was used to model hydration water fluctuations, ultrafast electron transfer in proteins, and photoreceptor’s initial primary processes. No code tweaking was required when moving from the Glenn Cluster to Oakley.

“The major challenge for our simulation is the large system size and long simulation time. Because we simulated a protein system with explicit hydration water, the whole hydrated system is very large in size, and we run the simulation to nanosecond (millions of steps). We take advantage of the supercomputer and parallel computation to get the simulation result in days [rather than months,” said Qin.

The research provides more compelling evidence for water’s active role in protein folding. Zhong explained that water can’t arbitrarily shape a protein. Proteins can only fold and unfold in a few different ways depending on the amino acids they’re made of. “Here, we’ve shown that the final shape of a protein depends on two things: water and the amino acids themselves. We can now say that, on ultrafast time scales, the protein surface fluctuations are controlled by water fluctuations. Water molecules work together like a big network to drive the movement of proteins.”

Here is a link to the paper: http://www.ncbi.nlm.nih.gov/pubmed/27339138

Here is a link to an article on the work on the OSC site: https://www.osc.edu/press/computer_simulations_help_scientists_glimpse_why_life_can%E2%80%99t_happen_without_water

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