He said what? DNA not a ‘stupid design’!

All right, time for a science rant.  I read Roberta Kwok’s recent Nature piece about scientists trying to improve on DNA’s structure and function, and I noted several overstatements and inaccuracies that had steam coming out of my ears.  To wit:

“The first thing you realize is that it is a stupid design,” says Benner, a biological chemist at the Foundation for Applied Molecular Evolution in Gainesville, Florida.

Take DNA’s backbone, which contains repeating, negatively charged phosphate groups. Because negative charges repel each other, this feature should make it harder for two DNA strands to stick together in a double helix. Then there are the two types of base-pairing: adenine (A) to thymine (T) and cytosine (C) to guanine (G). Both pairs are held together by hydrogen bonds, but those bonds are weak and easily broken up by water, something that the cell is full of. “You’re trusting your valuable genetic inheritance that you’re sending on to your children to hydrogen bonds in water?” says Benner. “If you were a chemist setting out to design this thing, you wouldn’t do it this way at all.”

As someone who has worked with DNA for most of my adult life, I have come to realize that many of the supposed “design problems” aren’t really problems first of all, and that the enzymes used to process DNA are responsible for many of the errors that are made in DNA biology.  Let’s start by unpacking the first sentence in the quote, the assertion that it’s a ‘stupid design’.  This is really just an unfortunate turn of phrase (probably).  Of course DNA wasn’t designed, because natural selection is not a deterministic process.  Where you end up depends on where you start and the precise path you take to get there, and stochasticity plays a major role at the molecular level.  I imagine Steven Benner knows and believes this, as most scientists do.  So, no biggie, other than being technically inaccurate for the sake of hype.

The second paragraph gets more grave in its fallacy, however.  Yes, DNA depends on hydrogen bonds that are broken up by water, but THIS IS WHY DNA WORKS THE WAY IT DOES, and it’s a VERY GOOD THING.  To see why this is true, we need to go back to the first law of thermodynamics.

The first law of thermodynamics tells us that energy is conserved between the Gibbs free energy, the change in useful enthalpy between the reactant and product states of a reaction; the enthalpy, that is the total amount of internal energy in a reaction, and the entropy, a measure of the disorder of the system, representing energy that is unrecoverable after a reaction.  We always speak in terms of changes in the these quantities, as absolute values cannot be measured directly:

First law of thermodyamics

Here ΔG is the change in Gibbs free energy, ΔH is the change in enthalpy, and ΔS is the change in internal entropy of the system.  To understand why DNA behaves the way it does, we need to look at these quantities as a function of the hybridization of DNA.  Let’s analyze the hybridization reaction of DNA in terms of this equation, starting with the Gibbs free energy change.

We know that negative values of ΔG represent spontaneous reactions, those that proceed on their own under the conditions of the reaction.  DNA hybridization is spontaneous, that is, two strands of complementary DNA will hybridize to each other in water under normal pressure and temperature conditions.  This challenges an implicit assertion in the article, that water somehow disrupts this base pairing.  Nope, hybridization happens just fine in water, and without it we wouldn’t exist, because DNA would never base pair to itself.  In fact, as we will see, the hydrogen bonds depend critically on the water for their formation.

To get a negative ΔG, we need the right side of the equation to be negative as well.  However, when we look at the entropy change, we notice that it is also negative, because by bringing two strands of DNA together, we have reduced the disorder of the system.  You can think about this as the number of ways the DNA molecules can move.  By themselves each molecule can move in more directions that when they are hybridized together – the double stranded DNA is more rigid than single strands.  A negative ΔS means that the -TΔS term is positive, working against our intended free energy change.  The fact that the backbones repel each other is reflected in this change in entropy as well.  The author is correct in saying that the two backbones repel one another, but then the argument goes off the rails.

To get a negative ΔG, the answer must therefore lie with the ΔH term, and indeed it does.  You can think of enthalpy as all the energy in all the bonds holding DNA together, as well as between a DNA strand and other molecules.  This includes DNA to DNA bonds (those pesky hydrogen bonds) and DNA to water,WHICH ARE ALSO HYDROGEN BONDS.  In the hybridization reaction, we form hydrogen bonds between the DNA strands, which takes energy, therefore making the change in enthalpy positive.  But:  to do this, we have to break lots more hydrogen bonds between the pesky charged DNA backbone and the water molecules.  This releases lots of energy, which makes the overall ΔH term large and negative.  So, for DNA to work the way it does, all features of DNA have to work together.  There has to be a charged backbone, hydrogen bond formation between strands, and the hybridization has to happen in water.  The assertion that hydrogen bonds between DNA molecules fall apart in water is false, unless the author meant in the kinetics sense (bonds are always breaking and reforming, but the equilibrium does not change).  Water is not harmful to DNA structure, in fact it defines it.

What the article was trying to say, I think, was that there are other ways to make ΔG negative.  Like, for example, if your ΔH term was less negative but your ΔS compensated for it.  Or, perhaps, if ΔH was even positive but -TΔS was strongly negative.  This is what scientists are trying to do when they change DNA’s alphabet.  To the article’s credit, this is stated in the quote from Gerald Joyce at Scripps:

“Earth has done it a certain way in its biology,” says Gerald Joyce, a nucleic-acid biochemist at the Scripps Research Institute in La Jolla, California. “But in principle there are other ways to achieve those ends.”

All this thermodynamics of DNA was laid bare in a great paper out of UBC in 1996 by my friends and colleagues Robin Turner and Charles Haynes.  The paper talks specifically about why DNA sticks to glass, but covers the thermodynamics of DNA in good detail.

I would have liked a bit more care in selecting quotes for the article, as it gives the impression that the scientists know a lot less than I think they do, and the result is misleading to any layperson who happens to pick it up.

OK, </rant>.

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