Ordovician Meteor Event

About 1/3 of the meteorites hitting Earth today come from one source: the L chondrite parent body, an asteroid 100–150 kilometers across that was smashed in an impact 468 million years ago. This was biggest asteroid collision in the last 3 billion years!

Here is an L-chondrite:

A chondrite is a stony, non-metallic meteorite that was formed form small grains of dust present in the early Solar System. They are the most common kind of meteorite—and the three most common kinds, each with its own somewhat different chemical composition, seem to come from different asteroids.

L chondrites are named that because they are low in iron. Compared to other chondrites, a lot of L chondrites have been heavily shocked—evidence that their parent body was catastrophically disrupted by a large impact.

It seems that roughly 500,000 years after this event, lots of meteorites started hitting Earth: this is called the Ordovician meteor event. Big craters from that event still dot the Earth! Here are some in North America:

Number 3 is the Rock Elm Disturbance, created when a rock roughly 170 meters in diameter slammed into what’s now Wisconsin:

It doesn’t look like much now, but imagine what it must have been like! The crater is about 6 kilometers across. It features intensely fractured quartz grain and a faulted rim.

It seems these big L-chondrite meteors hit the Earth roughly in a line:

Of course the continents didn’t look like this when the meteor hit, about 467.5 million years ago.

One big question is: was the Ordovician meteor event somehow connected to the giant increase in biodiversity during the Ordovician? Here’s a graph of biodiversity over time:

The Cambrian explosion gets all the press, but in terms of the sheer number of new families the so-called Ordovician radiation was bigger. Most animal life was undersea at the time. This is when coral reefs and other complex ocean ecosystems came into being!

There are lots of theories that try to explain the Ordovician radiation. For example, the oxygen concentration in the atmosphere and ocean soared right before the start of the Ordovician period. More than one of these theories could be right. But it’s interesting to think about the possible influence of the Ordovician meteor event.

There were a lot of meteor impacts, but the dust may have been more important. Right now, extraterrestrial dust counts for just 1% of all dust in the Earth’s atmosphere. In the Ordovician, the amount of extraterrestial dust was 1,000 – 10,000 times greater, due to the big smash-up in the asteroid belt! This may have caused the global cooling we see in that period. The Ordovician started out hot, but by the end there were glaciers.

How could this increase biodiversity? The “intermediate disturbance hypothesis” says that biodiversity increases under conditions of mild stress. Some argue this explains the Ordovician radiation.

I’d say this is pretty iffy. But it’s sure interesting! Read more here:

• Birger Schmitz et al., An extraterrestrial trigger for the mid-Ordovician ice age: Dust from the breakup of the L-chondrite parent body, Science Advances, 18 September 2019.

Another fun question is: where are the remains of the L chondrite parent body? Could they be the asteroids in the Flora family?

Coupling Through Emergent Conservation Laws (Part 8)

joint post with Jonathan Lorand, Blake Pollard, and Maru Sarazola

To wrap up this series, let’s look at an even more elaborate cycle of reactions featuring emergent conservation laws: the citric acid cycle. Here’s a picture of it from Stryer’s textbook Biochemistry:

I’ll warn you right now that we won’t draw any grand conclusions from this example: that’s why we left it out of our paper. Instead we’ll leave you with some questions we don’t know how to answer.

All known aerobic organisms use the citric cycle to convert energy derived from food into other useful forms. This cycle couples an exergonic reaction, the conversion of acetyl-CoA to CoA-SH, to endergonic reactions that produce ATP and a chemical called NADH.

The citric acid cycle can be described at various levels of detail, but at one level it consists of ten reactions:

Here are abbreviations for species that cycle around, each being transformed into the next. It doesn’t really matter for what we’ll be doing, but in case you’re curious:

• oxaloacetate,
• citrate,
• cis-aconitate,
• isocitrate,
• oxalosuccinate,
• α-ketoglutarate,
• succinyl-CoA,
• succinate,
• fumarate,
• L-malate.

In reality, the citric acid cycle also involves inflows of reactants such as acetyl-CoA, which is produced by metabolism, as well as outflows of both useful products such as ADP and NADH and waste products such as CO₂. Thus, a full analysis requires treating this cycle as an open chemical reaction network, where species flow in and out. However, we can gain some insight just by studying the emergent conservation laws present in this network, ignoring inflows and outflows—so let’s do that!

There are a total of 22 species in the citric acid cycle. There are 10 forward reactions. We can see that their vectors are all linearly independent as follows. Since each reaction turns into , where we count modulo 10, it is easy to see that any nine of the reaction vectors are linearly independent. Whichever one we choose to ‘close the cycle’ could in theory be linearly dependent on the rest. However, it is easy to see that the vector for this reaction

is linearly independent from the rest, because only this one involves FAD. So, all 10 reaction vectors are linearly independent, and the stoichiometric subspace has dimension 10.

Since 22 – 10 = 12, there must be 12 linearly independent conserved quantities. Some of these conservation laws are ‘fundamental’, at least by the standards of chemistry. All the species involved are made of 6 different atoms (carbon, hydrogen, oxygen, nitrogen, phosphorus and sulfur), and conservation of charge provides another fundamental conserved quantity, for a total of 7.

(In our example from last time we didn’t keep track of conservation of hydrogen and charge, because both and ions are freely available in water… but we studied the citric acid cycle when we were younger, more energetic and less wise, so we kept careful track of hydrogen and charge, and made sure that all the reactions conserved these. So, we’ll have 7 fundamental conserved quantities.)

For example, the conserved quantity

arises from the fact that , and contain a single sulfur atom, while none of the other species involved contain sulfur.

Similarly, the conserved quantity

expresses conservation of phosphorus.

Besides the 7 fundamental conserved quantities, there must also be 5 linearly independent emergent conserved quantities: that is, quantities that are not conserved in every possible chemical reaction, but remain constant in every reaction in the citric acid cycle. We can use these 5 quantities:

• , due to the conservation of adenosine.

• , due to conservation of flavin adenine dinucleotide.

• , due to conservation of nicotinamide adenine dinucleotide.

• . This expresses the fact that in the citric acid cycle each species is transformed to the next, modulo 10.

• . It can be checked by hand that each reaction in the citric acid cycle conserves this quantity. This expresses the fact that during the first 7 reactions of the citric acid cycle, one molecule of is destroyed and one molecule of is formed.

Of course, other conserved quantities can be formed as linear combinations of fundamental and emergent conserved quantities, often in nonobvious ways. An example is

which expresses the fact that in each turn of the citric acid cycle, one molecule of is destroyed and three of are formed. It is easier to check by hand that this quantity is conserved than to express it as an explicit linear combination of the 12 conserved quantities we have listed so far.

Finally, we bit you a fond farewell and leave you with this question: what exactly do the 7 emergent conservation laws do? In our previous two examples (ATP hydrolysis and the urea cycle) there were certain undesired reactions involving just the species we listed which were forbidden by the emergent conservation laws. In this case I don’t see any of those. But there are other important processes, involving additional species, that are forbidden. For example, if you let acetyl-CoA sit in water it will ‘hydrolyze’ as follows:

So, it’s turning into CoA-SH and some other stuff, somewhat as does in the citric acid cycle, but in a way that doesn’t do anything ‘useful’: no ATP or NADH is created in this process. This is one of the things the citric acid cycle tries to prevent.

(Remember, a reaction being ‘forbidden by emergent conservation laws’ doesn’t mean it’s absolutely forbidden. It just means that it happens much more slowly than the catalyzed reactions we are listing in our reaction network.)

Unfortunately acetate and aren’t on the list of species we’re considering. We could add them. If we added them, and perhaps other species, could we get a setup where every emergent conservation law could be seen as preventing a specific unwanted reaction that’s chemically allowed?

Ideally the dimension of the space of emergent conservation laws would match the dimension of the space spanned by reaction vectors of unwanted reactions, so ‘everything would be accounted for’. But even in the simpler example of the urea cycle, we didn’t achieve this perfect match.

 

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The paper:

• John Baez, Jonathan Lorand, Blake S. Pollard and Maru Sarazola,
Biochemical coupling through emergent conservation laws.

The blog series:

• Part 1 – Introduction.

• Part 2 – Review of reaction networks and equilibrium thermodynamics.

• Part 3 – What is coupling?

• Part 4 – Interactions.

• Part 5 – Coupling in quasiequilibrium states.

• Part 6 – Emergent conservation laws.

• Part 7 – The urea cycle.

• Part 8 – The citric acid cycle.

Coupling Through Emergent Conservation Laws (Part 7)

joint post with Jonathan Lorand, Blake Pollard, and Maru Sarazola

Last time we examined ATP hydrolysis as a simple example of coupling through emergent conservation laws, but the phenomenon is more general. A slightly more complicated example is the urea cycle. The first metabolic cycle to be discovered, it is used by land-dwelling vertebrates to convert ammonia, which is highly toxic, to urea for excretion. Now we’ll find 11 conserved quantities in the urea cycle, including 7 emergent ones.

(Yes, this post is about mathematics of piss!)

The urea cycle looks like this:

We’ll focus on this portion:

Ammonia () and carbonate () enter in the first reaction, along with ATP. The four remaining reactions form a cycle in which four similar species A₁, A₂, A₃, A₄ cycle around, each transformed into the next. In case you’re curious, these species are:

• A₁ = ornithine:

• A₂ = citrulline:

• A₃ = argininosuccinate:

• A₃ = arginine:

One atom of nitrogen from carbamoyl phosphate and one from aspartate enter this cycle, and they are incorporated in urea, which then leaves the cycle.

As you can see above, argininosuccinate is the largest of the four molecules that cycle around. It’s formed when citrulline combines with aspartate, which looks like this:

Argininosuccinate then breaks down to form arginine and fumarate:

All this is powered by two exergonic reactions: the hydrolysis of ATP to ADP and phosphate (P_i) and the hydrolysis of ATP to adenosine monophosphate (AMP) and a compound with two phosphorus atoms, pyrophosphate (PP_i). Thus, we are seeing a more elaborate example of an endergonic process coupled to ATP hydrolysis. The most interesting new feature is the use of a cycle.

Since inflows and outflows are crucial to the purpose of the urea cycle, a full analysis requires treating this cycle as an open chemical reaction network. However, we can gain some insight into coupling just by studying the emergent conservation laws present in this network, ignoring inflows and outflows.

There are a total of 16 species in the urea cycle. There are 5 forward reactions, which are easily seen to have linearly independent reaction vectors. Thus, the stoichiometric subspace has dimension 5. There must therefore be 11 linearly independent conserved quantities.

Some of these conserved quantities can be explained by fundamental laws of chemistry. All the species involved are made of five different atoms: carbon, hydrogen, oxygen, nitrogen and phosphorus. The conserved quantity

expresses conservation of phosphorus. The conserved quantity

expresses conservation of nitrogen. Conservation of oxygen and carbon give still more complicated conserved quantities. Conservation of hydrogen and conservation of charge are not really valid laws in this context, because all the reactions are occurring in water, where it is easy for protons (H⁺) and electrons to come and go. So, four linearly independent ‘fundamental’ conserved quantities are relevant to the urea cycle.

There must therefore be seven other linearly independent conserved quantities that are emergent: that is, not conserved in every possible reaction, but conserved by those in the urea cycle. A computer calculation shows that we can use these:

A) , due to conservation of adenosine by all reactions in the urea cycle.

B) , since the only reaction in the urea cycle involving either or has as a reactant and as a product.

C) , since the only reaction involving either or has as a reactant and as a product.

D) , since the only reaction involving either or has as a reactant and as a product.

E) , since the only reaction involving either or has as a reactant and as a product.

F) , since these species are involved only in the third and fourth reactions of the urea cycle, and this quantity is conserved in both those reactions.

G) , since these species cycle around the last four reactions, and they are not involved in the first.

These emergent conservation laws prevent either form of ATP hydrolysis from occurring on its own: the reaction

violates conservation of quantities B), D) and E), while

violates conservation of quantities B), C) and F). (In these reactions we are neglecting ions, since as mentioned these are freely available in water.)

Indeed, any linear combination of these two forms of ATP hydrolysis is prohibited. But since this requires only two emergent conservation laws, the presence of seven is a bit of a puzzle. Conserved quantity C) prevents the destruction of aspartate without the production of an equal amount of , conserved quantity D) prevents the destruction of without the production of an equal amount of , and so on. But there seems to be more coupling than is strictly “required”. Of course, many factors besides coupling are involved in an evolutionarily advantageous reaction network.

Further directions

Our paper, similar to these blog articles but with some more equations and fewer pictures, is here:

• John Baez, Jonathan Lorand, Blake S. Pollard and Maru Sarazola, Biochemical coupling through emergent conservation laws.

As a slight hint at further directions to explore, here’s an interesting quote:

“It is generally believed that enzyme-free prebiotic reactions typically go wild and produce many side products,” says Pasquale Stano, an organic chemist at the University of Salento, Italy.

Emergent conservation laws limit the number of side products! For more, see:

• Melissae Fellet, Enzyme-free reaction cycles hint at primitive precursor to metabolism, Chemistry World, 10 January 2018.

This is about an artificially created cycle similar to the citric acid cycle, which air-breathing organisms use to ‘burn’ foods and create ATP.

In our final post, we’ll take a look at the citric acid cycle and its emergent conservation laws. This material is more rough than the rest, and it didn’t find its way into our paper on the arXiv, but we put a fair amount of work into it—so, we’ll blog about it!

 

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The paper:

• John Baez, Jonathan Lorand, Blake S. Pollard and Maru Sarazola,
Biochemical coupling through emergent conservation laws.

The blog series:

• Part 1 – Introduction.

• Part 2 – Review of reaction networks and equilibrium thermodynamics.

• Part 3 – What is coupling?

• Part 4 – Interactions.

• Part 5 – Coupling in quasiequilibrium states.

• Part 6 – Emergent conservation laws.

• Part 7 – The urea cycle.

• Part 8 – The citric acid cycle.

Coupling Through Emergent Conservation Laws (Part 6)

joint post with Jonathan Lorand, Blake Pollard, and Maru Sarazola

Now let’s think about emergent conservation laws!

When a heavy rock connected to a lighter one by a pulley falls down and pulls up the lighter one, you’re seeing an emergent conservation law:

Here the height of the heavy rock plus the height of light one is a constant. That’s a conservation law! It forces some of the potential energy lost by one rock to be transferred to the other. But it’s not a fundamental conservation law, built into the fabric of physics. It’s an emergent law that holds only thanks to the clever design of the pulley. If the rope broke, this law would be broken too.

It’s not surprising that biology uses similar tricks. But let’s see exactly how it works. First let’s look at all four reactions we’ve been studying:

It’s easy to check that the rate equations for these reactions have the following conserved quantities, that is, quantities that are constant in time:

A) due to the conservation of X.

B) due to the conservation of Y.

C) due to the conservation of phosphorus.

D) due to the conservation of adenosine.

Moreover, these quantities, and their linear combinations, are the only conserved quantities for reactions (1)–(4).

To see this, we use some standard ideas from reaction network theory. Consider the 7-dimensional space with orthonormal basis given by the species in our reaction network:

We can think of complexes like as vectors in this space. An arbitrary choice of the concentrations of all species also defines a vector in this space. Furthermore, any reaction involving these species defines a vector in this space, namely the sum of the products minus the sum of the reactants. This is called the reaction vector of this reaction. Reactions (1)–(4) give these reaction vectors:

Any change in concentrations caused by these reactions must lie in the stoichiometric subspace: that is, the space spanned by the reaction vectors. Since these vectors obey one nontrivial relation:

the stochiometric subspace is 3-dimensional. Therefore, the space of conserved quantities must be 4-dimensional, since these specify the constraints on allowed changes in concentrations.

Now let’s compare the situation where ‘coupling’ occurs! For this we consider only reactions (3) and (4):

Now the stoichiometric subspace is 2-dimensional, since and are linearly independent. Thus, the space of conserved quantities becomes 5-dimensional! Indeed, we can find an additional conserved quantity:

E)

that is linearly independent from the four conserved quantities we had before. It does not derive from the conservation of a particular molecular component. In other words, conservation of this quantity is not a fundamental law of chemistry. Instead, it is an emergent conservation law, which holds thanks to the workings of the cell! It holds in situations where the rate constants of reactions catalyzed by the cell’s enzymes are so much larger than those of other reactions that we can ignore those other reactions.

And remember from last time: these are precisely the situations where we have coupling.

Indeed, the emergent conserved quantity E) precisely captures the phenomenon of coupling! The only way for ATP to form ADP + P_i without changing this quantity is for Y to be consumed in the same amount as P_i is created… thus forming the desired product XY.

Next time we’ll look at a more complicated example from biology: the urea cycle.

 

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The paper:

• John Baez, Jonathan Lorand, Blake S. Pollard and Maru Sarazola,
Biochemical coupling through emergent conservation laws.

The blog series:

• Part 1 – Introduction.

• Part 2 – Review of reaction networks and equilibrium thermodynamics.

• Part 3 – What is coupling?

• Part 4 – Interactions.

• Part 5 – Coupling in quasiequilibrium states.

• Part 6 – Emergent conservation laws.

• Part 7 – The urea cycle.

• Part 8 – The citric acid cycle.

Coupling Through Emergent Conservation Laws (Part 5)

joint post with Jonathan Lorand, Blake Pollard, and Maru Sarazola

Coupling is the way biology makes reactions that ‘want’ to happen push forward desirable reactions that don’t want to happen. Coupling is achieved through the action of enzymes—but in a subtle way. An enzyme can increase the rate constant of a reaction. However, it cannot change the ratio of forward to reverse rate constants, since that is fixed by the difference of free energies, as we saw in Part 2:

and the presence of an enzyme does not change this.

Indeed, if an enzyme could change this ratio, there would be no need for coupling! For example, increasing the ratio in the reaction

would favor the formation of XY, as desired. But this option is not available.

Instead, to achieve coupling, the cell uses enyzmes to greatly increase both the forward and reverse rate constants for some reactions while leaving those for others unchanged!

Let’s see how this works. In our example, the cell is trying to couple ATP hydrolysis to the formation of the molecule XY from two smaller parts X and Y. These reactions don’t help do that:

but these do:

So, the cell uses enzymes to make the rate constants for reactions (3) and (4) much bigger than for (1) and (2). In this situation we can ignore reactions (1) and (2) and still have a good approximate description of the dynamics, at least for sufficiently short time scales.

Thus, we shall study quasiequilibria, namely steady states of the rate equation for reactions (3) and (4) but not (1) and (2). In this approximation, the relevant Petri net becomes this:

Now it is impossible for ATP to turn into ADP + P_i without X + Y also turning into XY. As we shall see, this is the key to coupling!

In quasiequilibrium states, we shall find a nontrivial relation between the ratios and . This lets the cell increase the amount of XY that gets made by increasing the amount of ATP present.

Of course, this is just part of the full story. Over longer time scales, reactions (1) and (2) become important. They would drive the system toward a true equilibrium, and destroy coupling, if there were not an inflow of the reactants ATP, X and Y and an outflow of the products P_i and XY. To take these inflows and outflows into account, we need the theory of ‘open’ reaction networks… which is something I’m very interested in!

But this is beyond our scope here. We only consider reactions (3) and (4), which give the following rate equation:

Quasiequilibria occur when all these time derivatives vanish. This happens when

This pair of equations is equivalent to

and it implies

If we forget about the species XP_i (whose presence is crucial for the coupling to happen, but whose concentration we do not care about), the quasiequilibrium does not impose any conditions other than the above relation. We conclude that, under these circumstances and assuming we can increase the ratio

it is possible to increase the ratio

This constitutes ‘coupling’.

We can say a bit more, since we can express the ratios of forward and reverse rate constants in terms of exponentials of free energy differences using the laws of thermodynamics, as explained in Part 2. Reactions (1) and (2), taken together, convert X + Y + ATP to XY + ADP + P_i. So do reactions (3) and (4) taken together. Thus, these two pairs of reactions involve the same total change in free energy, so

But we’re also assuming ATP hydrolysis is so strongly exergonic that

This implies that

Thus,

This is why coupling to ATP hydrolysis is so good at driving the synthesis of XY from X and Y! Ultimately, this inequality arises from the fact that the decrease in free energy for the reaction

greatly exceeds the increase in free energy for the reaction

But this fact can only be put to use in the right conditions. We need to be in a ‘quasiequilibrium’ state, where fast reactions have reached a steady state but not slow ones. And we need fast reactions to have this property: they can only turn ATP into ADP + P_i if they also turn X + Y into XY. Under these conditions, we have ‘coupling’.

Next time we’ll see how coupling relies on an ’emergent conservation law’.

 

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The paper:

• John Baez, Jonathan Lorand, Blake S. Pollard and Maru Sarazola,
Biochemical coupling through emergent conservation laws.

The blog series:

• Part 1 – Introduction.

• Part 2 – Review of reaction networks and equilibrium thermodynamics.

• Part 3 – What is coupling?

• Part 4 – Interactions.

• Part 5 – Coupling in quasiequilibrium states.

• Part 6 – Emergent conservation laws.

• Part 7 – The urea cycle.

• Part 8 – The citric acid cycle.

Coupling Through Emergent Conservation Laws (Part 4)

joint post with Jonathan Lorand, Blake Pollard, and Maru Sarazola

We’ve been trying to understand coupling: how a chemical reaction that ‘wants to happen’ because it decreases the amount of free energy can drive forward a chemical reaction that increases free energy.

For coupling to occur, the reactant species in both reactions must interact in some way. Indeed, in real-world examples where ATP hydrolysis is coupled to the formation of larger molecule from parts and it is observed that, aside from the reactions we discussed last time:

two other reactions (and their reverses) take place:

We can picture all four reactions (1-4) in a single Petri net as follows:

Taking into account this more complicated set of reactions, which are interacting with each other, is still not enough to explain the phenomenon of coupling. To see this, let’s consider the rate equation for the system comprised of all four reactions. To write it down neatly, let’s introduce reaction velocities that say the rate at which each forward reaction is taking place, minus the rate of the reverse reaction:

All these follow from the law of mass action, which we explained in Part 2. Remember, this says that any reaction occurs at a rate equal to its rate constant times the product of the concentrations of the species involved. So, for example, this reaction

goes forward at a rate equal to , while the reverse reaction occurs at a rate equal to So, its reaction velocity is

In terms of these reaction velocities, we can write the rate equation as follows:

This makes sense if you think a bit: it says how each reaction contributes to the formation or destruction of each species.

In a steady state, all these time derivatives are zero, so we must have

Furthermore, in a detailed balanced equilibrium, every reaction occurs at the same rate as its reverse reaction, so all four reaction velocities vanish! In thermodynamics, a system that’s truly in equilibrium obeys this sort of detailed balance condition.

When all the reaction velocities vanish, we have:

Thus, even when the reactants interact, there can be no coupling if the whole system is in equilibrium, since then the ratio is still forced to be . This is obvious to anyone who truly understands what Boltzmann and Gibbs did. But here we saw it in detail.

The moral is that coupling cannot occur in equilibrium. But how, precisely, does coupling occur? Stay tuned!

 

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The paper:

• John Baez, Jonathan Lorand, Blake S. Pollard and Maru Sarazola,
Biochemical coupling through emergent conservation laws.

The blog series:

• Part 1 – Introduction.

• Part 2 – Review of reaction networks and equilibrium thermodynamics.

• Part 3 – What is coupling?

• Part 4 – Interactions.

• Part 5 – Coupling in quasiequilibrium states.

• Part 6 – Emergent conservation laws.

• Part 7 – The urea cycle.

• Part 8 – The citric acid cycle.

Coupling Through Emergent Conservation Laws (Part 3)

joint post with Jonathan Lorand, Blake Pollard, and Maru Sarazola

Last time we gave a quick intro to the chemistry and thermodynamics we’ll use to understand ‘coupling’. Now let’s really get started!

Suppose that we are in a setting in which some reaction

takes place. Let’s also assume we are interested in the production of from and but that in our system, the reverse reaction is favored to happen. This means that that reverse rate constant exceeds the forward one, let’s say by a lot:

so that in equilibrium, the concentrations of the species will satisfy

which we assume undesirable. How can we influence this ratio to get a more desired outcome?

This is where coupling comes into play. Informally, we think of the coupling of two reactions as a process in which an endergonic reaction—one which does not ‘want’ to happen—is combined with an exergonic reaction—one that does ‘want’ to happen—in a way that improves the products-to-reactants concentrations ratio of the first reaction.

An important example of coupling, and one we will focus on, involves ATP hydrolysis:

where ATP (adenosine triphosphate) reacts with a water molecule. Typically, this reaction results in ADP (adenosine diphosphate), a phosphate ion and a hydrogen ion To simplify calculations, we will replace the above equation with

since suppressing the bookkeeping of hydrogen and oxygen atoms in this manner will not affect our main points.

One reason ATP hydrolysis is good for coupling is that this reaction is strongly exergonic:

and in fact so much that

Yet this fact alone is insufficient to explain coupling!

To see why, suppose our system consists merely of the two reactions

happening in parallel. We can study the concentrations in equilibrium to see that one reaction has no influence on the other. Indeed, the rate equation for this reaction network is

When concentrations are constant, these are equivalent to the relations

We thus see that ATP hydrolysis is in no way affecting the ratio of to Intuitively, there is no coupling because the two reactions proceed independently. This ‘independence’ is clearly visible if we draw the reaction network as a so-called Petri net:

So what really happens when we are in the presence of coupling? Stay tuned for the next episode!

By the way, here’s what ATP hydrolysis looks like in a bit more detail, from a website at Loreto College:

 

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The paper:

• John Baez, Jonathan Lorand, Blake S. Pollard and Maru Sarazola,
Biochemical coupling through emergent conservation laws.

The blog series:

• Part 1 – Introduction.

• Part 2 – Review of reaction networks and equilibrium thermodynamics.

• Part 3 – What is coupling?

• Part 4 – Interactions.

• Part 5 – Coupling in quasiequilibrium states.

• Part 6 – Emergent conservation laws.

• Part 7 – The urea cycle.

• Part 8 – The citric acid cycle.

Coupling Through Emergent Conservation Laws (Part 2)

joint post with Jonathan Lorand, Blake Pollard, and Maru Sarazola

Here’s a little introduction to the chemistry and thermodynamics prerequisites for our work on ‘coupling’. Luckily, it’s fun stuff that everyone should know: a lot of the world runs on these principles!

We will be working with reaction networks. A reaction network consists of a set of reactions, for example

Here X, Y and XY are the species involved, and we interpret this reaction as species X and Y combining to form species XY. We call X and Y the reactants and XY the product. Additive combinations of species, such as X + Y, are called complexes.

The law of mass action states that the rate at which a reaction occurs is proportional to the product of the concentrations of the reactants. The proportionality constant is called the rate constant; it is a positive real number associated to a reaction that depends on chemical properties of the reaction along with the temperature, the pH of the solution, the nature of any catalysts that may be present, and so on. Every reaction has a reverse reaction; that is, if X and Y combine to form XY, then XY can also split into X and Y. The reverse reaction has its own rate constant.

We can summarize this information by writing

where is the rate constant for X and Y to combine and form XY, while is the rate constant for the reverse reaction.

As time passes and reactions occur, the concentration of each species will likely change. We can record this information in a collection of functions

one for each species where gives the concentration of the species at time This naturally leads one to consider the rate equation of a given reaction, which specifies the time evolution of these concentrations. The rate equation can be read off from the reaction network, and in the above example it is:

Here is the rate at which the forward reaction is occurring; thanks to the law of mass action, this is the rate constant times the product of the concentrations of X and Y. Similarly, is the rate at which the reverse reaction is occurring.

We say that a system is in detailed balanced equilibrium, or simply equilibrium, when every reaction occurs at the same rate as its reverse reaction. This implies that the concentration of each species is constant in time. In our example, the condition for equilibrium is

and the rate equation then implies that

The laws of thermodynamics determine the ratio of the forward and reverse rate constants. For any reaction at all, this ratio is

where is the temperature, is the ideal gas constant, and is the free energy change under standard conditions.

Note that if , then the rate constant of the forward reaction is larger than the rate constant of the reverse reaction:

In this case one may loosely say that the forward reaction ‘wants’ to happen ‘spontaneously’. Such a reaction is called exergonic. If on the other hand , then the forward reaction is ‘non-spontaneous’ and it is called endergonic.

The most important thing for us is that takes a very simple form. Each species has a free energy. The free energy of a complex

is the sum of the free energies of the species . Given a reaction

the free energy change for this reaction is the free energy of

minus the free energy of

As a consequence, is additive with respect to combining multiple reactions in either series or parallel. In particular, then, the law (1) imposes relations between ratios of rate constants: for example, if we have the following more complicated set of reactions

then we must have

So, not only are the rate constant ratios of reactions determined by differences in free energy, but also nontrivial relations between these ratios can arise, depending on the structure of the system of reactions in question!

Okay—this is all the basic stuff we’ll need to know. Please ask questions! Next time we’ll go ahead and use this stuff to start thinking about how biology manages to make reactions that ‘want’ to happen push forward reactions that are useful but wouldn’t happen spontaneously on their own.

 

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The paper:

• John Baez, Jonathan Lorand, Blake S. Pollard and Maru Sarazola,
Biochemical coupling through emergent conservation laws.

The blog series:

• Part 1 – Introduction.

• Part 2 – Review of reaction networks and equilibrium thermodynamics.

• Part 3 – What is coupling?

• Part 4 – Interactions.

• Part 5 – Coupling in quasiequilibrium states.

• Part 6 – Emergent conservation laws.

• Part 7 – The urea cycle.

• Part 8 – The citric acid cycle.

Coupling Through Emergent Conservation Laws (Part 1)

joint post with Jonathan Lorand, Blake Pollard, and Maru Sarazola

In the cell, chemical reactions are often ‘coupled’ so that reactions that release energy drive reactions that are biologically useful but involve an increase in energy. But how, exactly, does coupling work?

Much is known about this question, but the literature is also full of vague explanations and oversimplifications. Coupling cannot occur in equilibrium; it arises in open systems, where the concentrations of certain chemicals are held out of equilibrium due to flows in and out. One might thus suspect that the simplest mathematical treatment of this phenomenon would involve non-equilibrium steady states of open systems. However, Bazhin has shown that some crucial aspects of coupling arise in an even simpler framework:

• Nicolai Bazhin, The essence of ATP coupling, ISRN Biochemistry 2012 (2012), article 827604.

He considers ‘quasi-equilibrium’ states, where fast reactions have come into equilibrium and slow ones are neglected. He shows that coupling occurs already in this simple approximation.

In this series of blog articles we’ll do two things. First, we’ll review Bazhin’s work in a way that readers with no training in biology or chemistry should be able to follow. (But if you get stuck, ask questions!) Second, we’ll explain a fact that seems to have received insufficient attention: in many cases, coupling relies on emergent conservation laws.

Conservation laws are important throughout science. Besides those that are built into the fabric of physics, such as conservation of energy and momentum, there are also many ’emergent’ conservation laws that hold approximately in certain circumstances. Often these arise when processes that change a given quantity happen very slowly. For example, the most common isotope of uranium decays into lead with a half-life of about 4 billion years—but for the purposes of chemical experiments in the laboratory, it is useful to treat the amount of uranium as a conserved quantity.

The emergent conservation laws involved in biochemical coupling are of a different nature. Instead of making the processes that violate these laws happen more slowly, the cell uses enzymes to make other processes happen more quickly. At the time scales relevant to cellular metabolism, the fast processes dominate, while slowly changing quantities are effectively conserved. By a suitable choice of these emergent conserved quantities, the cell ensures that certain reactions that release energy can only occur when other ‘desired’ reactions occur. To be sure, this is only approximately true, on sufficiently short time scales. But this approximation is enlightening!

Following Bazhin, our main example involves ATP hydrolysis. We consider this following schema for a whole family of reactions:

Some concrete examples of this schema include:

• The synthesis of glutamine (XY) from glutamate (X) and ammonium (Y). This is part of the important glutamate-glutamine cycle in the central nervous system.

• The synthesis of sucrose (XY) from glucose (X) and fructose (Y). This is one of many processes whereby plants synthesize more complex sugars and starches from simpler building-blocks.

In these and other examples, the two reactions, taken together, have the effect of synthesizing a larger molecule XY out of two parts X and Y while ATP is broken down to ADP and the phosphate ion P_i Thus, they have the same net effect as this other pair of reactions:

The first reaction here is just the synthesis of XY from X and Y. The second is a deliberately simplified version of ATP hydrolysis. The first involves an increase of energy, while the second releases energy. But in the schema used in biology, these processes are ‘coupled’ so that ATP can only break down to ADP + P_i if X and Y combine to form XY.

As we shall see, this coupling crucially relies on a conserved quantity: the total number of Y molecules plus the total number of P_i ions is left unchanged by reactions (1) and (2). This fact is not a fundamental law of physics, nor even a general law of chemistry (such as conservation of phosphorus atoms). It is an emergent conservation law that holds approximately in special situations. Its approximate validity relies on the fact that the cell has enzymes that make reactions (1) and (2) occur more rapidly than reactions that violate this law, such as (3) and (4).

In the series to come, we’ll start by providing the tiny amount of chemistry and thermodynamics needed to understand what’s going on. Then we’ll raise the question “what is coupling?” Then we’ll study the reactions required for coupling ATP hydrolysis to the synthesis of XY from components X and Y, and explain why these reactions are not yet enough for coupling. Then we’ll show that coupling occurs in a ‘quasiequilibrium’ state where reactions (1) and (2), assumed much faster than the rest, have reached equilibrium, while the rest are neglected. And then we’ll explain the role of emergent conservation laws!

 

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The paper:

• John Baez, Jonathan Lorand, Blake S. Pollard and Maru Sarazola,
Biochemical coupling through emergent conservation laws.

The blog series:

• Part 1 – Introduction.

• Part 2 – Review of reaction networks and equilibrium thermodynamics.

• Part 3 – What is coupling?

• Part 4 – Interactions.

• Part 5 – Coupling in quasiequilibrium states.

• Part 6 – Emergent conservation laws.

• Part 7 – The urea cycle.

• Part 8 – The citric acid cycle.

A Biochemistry Question

Does anyone know a real-world example of a cycle like this:

or in other words, this:

where the reaction

is exergonic (i.e., involves a decrease in free energy) while

is endergonic (i.e., involves a free energy increase)?

The idea is that the above cycle, presumably catalyzed so that all the reactions go fairly fast under normal conditions, ‘couples’ the exergonic reaction, which ‘wants to happen’, to the endergonic reaction, which doesn’t… thus driving the endergonic one.

I would love an example from biochemistry. This is like a baby version of much more elaborate cycles such as the citric acid cycle, shown here:

in a picture from Stryer’s Biochemistry. I’m writing a paper on this stuff with Jonathan Lorand, Blake Pollard and Maru Sarazola, and we have—presumably obvious—reasons to want to discuss a simpler cycle!