One of the major quests of protein structural biology is to understand the most fundamental aspect of protein folding: how does a stretch of amino acids assemble itself from random coils to a complex three-dimensional structure? And what is the driving force behind the process? Despite the fact that proteins are evolutionarily favored to ‘collapse’ into the most energetically favored conformation, molecules in their immediate environment, such as water, influence two key aspects of the process: folding time, and the spatial orientation of amino acids in the folding protein.
Another impressive facet of the folding process is the time-scale of folding, which is typically within the range of nanoseconds. And water molecules flow around each other within picoseconds, which is 1,000 times faster than the protein folding time. This offers a major challenge to directly study any water-protein interactions that drive the process.
Though water has long been inferred to be pivotal in protein folding, the current research published in the Proceedings of the National Academy of Sciences provides the most direct evidence yet of this. Scientists from the Ohio State University used ultra-fast laser pulses to ‘see’ how water molecules move around the global surface of a folding protein. To render the protein visible to their technique, the researchers inserted optical probes (tryptophan residues) within key locations on the surface of the protein DNA polymerase, and measured water movement around them. Water molecules surrounding a protein form a hydration shell around the surface.
Using computer simulations, the scientists were able to model the behavior of water molecules within the protein’s hydration shell and their interactions with the protein’s side-chains. They concluded from the concerted movement of these water molecules and protein side-chain fluctuations that the two processes were energetically coupled. Water rapidly interacted and disengaged with the protein side-chains, appearing to nudge the protein into shape.
“Here, we’ve shown that the final shape of a protein depends on two things: water and the amino acids themselves.” Dongping Zhong, lead researcher of the study. “We can now say that, on ultra-fast 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.”
“We believe we now have strong direct evidence that on ultra-fast time scales (picoseconds, or trillionths of a second), water modulates protein fluctuations,” concluded Dr. Zhong.
The press release may be accessed here.
Link to the original research article – PNAS