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The Wonder of Water at the Nanoscale

Evolution News


The last chapter of Michael Denton’s latest book, The Wonder of Water (which we’ll abbreviate WoW, and yes, the pun is intended), is the grand slam that runs home all the bases. After showing water’s incomparable role in climate, geology, and physiology, he looks deep into the cell and shows that water’s unique properties contribute to life at the nanoscale of molecular interactions. In “Water and the Cell” (especially pp. 168-177), Denton shows that H2O has been promoted from cellular stage hand to prima donna:

Water is fit for cellular physiology and biochemistry for many reasons: it has great solvation powers for all charged and polar compounds, its viscosity is right, and so forth. But water is far more than just a passive matrix. Water plays so many well-understood key roles in active processes, such as folding proteins, assembling cell membranes, and providing proton flows (especially proton flows in which water is clearly a key player if not the key player in bioenergetics), that it is already clear that it is indeed the active player in cellular physiology that Szent-Győrgi envisaged when he said, “Life is water, dancing to the tune of solids.” [Emphasis added.]

This hyperbole is not meant to discount the essential role of coded information in the cell, as ID science reminds us; but as we shall see, water plays essential roles in the transfer of information in proteins and other biomolecules. Its ability to do this arises from the properties Denton discusses in chapter 7, such as viscosity, metastability and temperature range as a liquid, but it plays out in unexpected ways, some of them “well understood” but others at the frontier of biophysics.

A series of papers presented in December 2017 by the Proceedings of the National Academy of Sciences (PNAS) shows that much work needs to be done to understand water. In their introductory paper, “Chemical physics of water,” Pablo G. Debenedettia and Michael L. Klein begin with some Denton-esque WoW:

There is hardly any aspect of our lives that is not profoundly influenced by water. From climate to commerce and agriculture to health, water shapes our physical environment, regulates the major energy exchanges that determine climate on Earth, and is the matrix that supports the physical and chemical processes of life as we know it. The chemistry and physics of water, which underlie all of its uses, its necessity for life, its effects on other molecules and on the environment, are very active areas of research at the present time. So, why is this? Surprisingly, there are major gaps in knowledge and understanding that persist despite this substance’s ubiquity and central importance.

Among the ten papers that rise to the challenge is an opening perspective article by science journalist Philip Ball, “Water is an active matrix of life for cell and molecular biology.” Ball has a particular fascination with this topic, which apparently has grown over the last decade (Denton references his 2008 paper on the subject). Now he has additional data to confirm water’s “dance” with proteins as an active partner. This is best appreciated with some examples. First, he sets the stage. Notice his mention of information:

Water exhibits diverse structural and dynamical roles in molecular cell biology. It conditions and in fact partakes in the motions on which biomolecular interactions depend. It is the source of one of the key forces that dictate macromolecular conformations and associations, namely the hydrophobic attraction. It forms an extraordinary range of structures, most of them transient, that assist chemical and information-transfer processes in the cell. It acts as a reactive nucleophile and proton donor and acceptor, it mediates electrostatic interactions, and it undergoes fluctuations and abrupt phase-transition — like changes that serve biological functions. Is it not rather remarkable that a single and apparently rather simple molecular substance can accomplish all of these things? Looked at this way, there does seem to be something special about water.

Before proceeding to examples, we should look at water not as individual molecules, but a dynamic network. Because water is a polar molecule, its “electrostatic interactions” come from hydrogen bonds with itself and with other molecules. The dynamic network of water molecules adapts to the surfaces of cellular components, attracted to hydrophilic (water-loving) points and resisting hydrophobic (water-hating) points. In a related paper in the PNAS special feature, Xi et al. experimented with artificial surfaces and with mutated proteins to try to measure how shape and amino acid position affect hydrophobicity. By their own admission, this is a “major challenge” that their efforts only bluntly addressed. Nevertheless, we need to see the typical maps of proteins as incomplete without their “hydration haloes” attached.

Hydrophobicity Facilitates Protein Hydraulics

Many proteins are known to undergo “conformational changes” (jargon for “moving parts”) essential to their functions. We’ve seen that in classic molecular machines that are icons of intelligent design, like kinesin and ATP synthase. While many of these motions use the energy of ATP, increasingly biochemists are appreciating water’s role in these movements. This is not due to simple lubrication, but from electrostatic and hydrophobic reactions in the protein environment.

One example is protein folding: “The attraction of hydrophobes in water is well-attested and is one of the key driving forces for protein folding and the formation of functional multiprotein aggregates,” Ball says. This “driving force” from hydrophobicity can actually take on a more elegant and positive functional role, however. They hydration halo around a protein gives it a greater sphere of influence.

Hydration water molecules may adopt crystallographically well-defined positions around a macromolecule, and some of these have functional roles. One might say that the surfaces of the biomolecules are not sharply defined: their sphere of influence extends beyond the van der Waals surface into the solvent, and this coupling can make the hydration shell for all intents and purposes part of the biomolecule itself, imbued with some of the information that it encodes and therefore able to play a role in intramolecular rearrangements and intermolecular recognition processes.

Ball gives some recent examples. Some are quite fascinating. Water can facilitate large-scale movements of proteins, as in this example of hydraulic power:

In the hexameric multidomain protein glutamate dehydrogenase, the opening and closing of a hydrophobic pocket are accompanied by wetting and drying of the pocket, whereas binding and unbinding of water molecules in a hydrophilic crevice accompany changes in its length. These two changes in hydration are coupled, creating a kind of “hydraulic” mechanism for large-scale conformational change.

This raises an interesting question for ID research: Do genes take into account the action of water molecules as they construct molecular machines?

Water Transmits Electrical Power

Denton briefly mentioned “proton wires” made of water molecules that efficiently transmit protons without the need for conformational changes (pp 173-174). This form of energy transfer, because it affects protein function, amounts to information transfer as well. It comes directly out of water’s hydrogen-bonding ability. Ball gives the example of Complex I, an essential enzyme in respiration. “Water wires” in this molecular machine are part of its proton pumping function. “Here, a transient proton-conducting water channel is formed by the cooperative hydration of three antiporter-like subunits within the membrane domain of the complex.” Another example has the delicacy of a Debussy Nocturne:

Delicate marshaling of water molecules into positions that control the proton conductivity of a channel is also evident in cytochrome c oxidase, a transmembrane proton pump driven by oxygen reduction. Goyal et al. show how hydration seems to carefully tune and orchestrate this proton translocation. A glutamate residue is believed to act as a temporary proton donor, and its proton affinity is controlled by the degree of hydration in an internal hydrophobic cavity. That hydration, in turn, is governed by protonation of a substituent on the heme group 10 Å away, triggering movement of a loop that gates the cavity’s entrance.

Water Increases Active Site Functionality

The active site of a protein can be enhanced by its hydration halo. Here’s an example:

Water can help to fine-tune protein functionality in a variety of ways. It seems, for example, to enable the promiscuity of alkaline phosphatase enzymes in catalyzing the hydrolysis of a range of different phosphate and sulfate substrates. First principles simulations suggest that a part of the reason why this class of enzymes can support different types of transition state in the same active site is the differential placement of water molecules. Another form of “hydration tuning” is revealed in the chloride-pumping transmembrane retinal protein halorhodopsin of halophiles. Here, subtle rearrangements of waters and ions occur in the vicinity of the chromophore as chloride translocation progresses, inducing changes in chromophore bond lengths that affect its absorption spectrum.

One other example of the functional role of a hydration network is found in antifreeze proteins. We know that water crystals during freezing can disrupt cells, but water molecules working in concert with proteins can actually disrupt freezing:

The involvement of bound water can be more exotic. The fish antifreeze protein Maxi is a four-helix bundle with an interior, mostly hydrophobic channel filled with more than 400 water molecules, crystallographically ordered into a clathrate-like network of predominantly five-membered rings. It seems that this ordered network extends outward through the gaps between the helices to create an ordered layer of water molecules on the outer surface that enables Maxi to bind to ice crystals and hinder their growth, acting as a kind of “molecular Velcro” for ice binding.


Ball ends with the astrobiological question of whether life could arise on other planets without water. It’s hard to answer, he says, given water’s dynamic nature, and some have gone too far by ascribing mystical powers to “biological water,” to the point of mythology. But his gut feel is that it’s riskier to underestimate the importance of water:

However, if we should abandon notions of some special and well-defined phase called biological water, there does not seem to be any prospect of or virtue in returning water to its humble position of life’s canvas. It is a versatile, responsive medium that blurs the boundaries between mechanism and matrix. It surely is special; we might have to depend on either synthetic biology or observational astrobiology to tell us just how special.

Water, indeed, appears very special at the nanoscale. Denton, however, expands its specialness to the planetary scale and all scales in between, showing a multitude of essential roles for this amazing molecule that makes our planet not only habitable, but enjoyable. There’s nothing mystical about that when considered from a design perspective.

Image: “How to Build a Cell,” from Origin: Design, Chance, and the First Life on Earth, courtesy of Illustra Media.