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Thursday, September 04, 2008

The Demise of the Squiggle

Fritz Lipmann is often credited with discovering ATP but that's not correct. He won his Nobel Prize for discovering Coenzyme A [The Nobel Prize in Physiology or Medicine 1953].

However, it's fair to say that Lipmann made some of the most important contributions to our understanding of ATP as an energy currency. His classic 1941 paper in Advances in Enzymology was entitled "Metabolic Generation and Utilization of Phosphate Bond Energy." In that paper he introduced the concept of an energy-rich phosphate bond designated by a squiggle (~). Thus ATP could be represented as


to show that it had two such high energy bonds. The cleavage of either bond is accompanied by a large release of energy that's available to do work. The idea that ATP contained some special bonds with high energy was very attractive and the concept ruled in biochemistry textbooks for several decades. Indeed, there are still many courses and websites that still use the squiggle.

The concept is extremely misleading and came under attack by many biochemists in the 1950s and 60s. According to these biochemists, the correct way of looking at ATP as an energy currency is to recognize that the overall reaction of hydrolysis is associated with a large negative Gibbs free energy change.

ATP + H2O → ADP + Pi          ΔG°′ = -32 kJ mol-1

It's the system, including reactants and products, that is associated with the large negative free energy change. The only reason ATP is useful as an energy currency is because the concentration of ATP is maintained at high levels relative to ADP + Pi inside the cell. As a matter of fact, the actual Gibbs free energy change in vivo is closer to -48 kJ mol-1.

If the system were allowed to reach equilibrium then ΔG°′ = 0. Think about what this means. At equilibrium those ~P "high energy" bonds are still being broken but there's no useful energy being produced.

Does this mean that the strength of a chemical bond depends on the relative concentration of reactants and products? Of course not. What it means, in the words of someone who knew Friz Lipmann, is that his understanding of basic thermodynamics was rudimentary.

The arguments over the proper way to think about ATP raged back and forth in the scientific literature for over thirty years. For the most part Lipmann did not participate in the squiggle debates, he left his defense to others. It's fair to say that there was no knock-out blow that ended the fight. Gradually people began to realize that the squiggle—and the concept of a high energy bond—were unfortunate at best and possibly misleading to the point of being counter-productive. The squiggle has been dropped from most (all?) textbooks.

So, how do we explain the fact that ATP hydrolysis is associated with a large release of energy under conditions found inside the cell? If it's not because of some special "high energy" bond, then what is it? See Why Is ATP an Important Energy Currency in Biochemistry?.

Here's a couple of articles on the history of the squiggle:

Fritz Lipmann

Power, Sex, Suicide: Mitochondria and the Meaning of Life: The elusive squiggle (p.80>)

Here are some websites that still refer to "high-energy" bonds and still use the squiggle. It's interesting that most of these sites include a modest disclaimer, stating that there's no such thing as a "high-energy bond" but they then go on to talk about high energy bonds using the squiggle notation.

Rensselaer Polytechnic Institute

Columbia University

University of Connecticut

Online Textbook: Department of School Education, Govt. of Tamil Nadu, India

[I am indebted to my colleague Byron Lane for explaining the history to me. He was a post-doc in the Lipmann lab during the 1950s where he was in a position to observe the debate first-hand. Byron kindly gave me copies of the relevant papers. Our discussion began when we realized that the kinds of scientific debates that were common in the past are no longer occurring even though there are many controversies bubbling beneath the surface. We don't know why. Does anyone?]


TheBrummell said...

Our discussion began when we realized that the kinds of scientific debates that were common in the past are no longer occurring even though there are many controversies bubbling beneath the surface.

That's an interesting assertion. Do you have examples of modern controversies that are not currently subject to debate of the type exemplified by the squiggle / high energy bond?

Larry Moran said...

An interesting example was the number of genes in the human genome. Before the human genome project was finished there was considerable disagreement among scientists but, for the most part, that dispute never made it into the scientific literature.

There was a famous lottery but no real debate [Facts and Myths Concerning the Historical Estimates of the Number of Genes in the Human Genome].

Current examples include: (1) the importance and significance of alternative splicing, (2) the importance and significance of small RNAs, (3) evolutionary psychology, (4) the meaning of the Central Dogma, and many others.

In all these cases you would be hard pressed to find papers in the scientific literature that were as blunt and hard-hitting in their criticisms as some of those that have appeared during past controversies. This is in spite of the fact that there is considerable disagreement among scientists.

There seems to be a general trend toward being "nice" these days even if it means keeping our mouth shut when colleagues say really, really stupid things. The days when Francis Crick could stand up at a meeting and say "This is no place for amateurs" have gone.