Who's afraid of Big Bad Thermodynamics?

George Whitesides, in a trademark outfit.

In a talk at Northeastern University yesterday, George Whitesides asked the students in the audience if they had ever studied thermodynamics. Not a single hand went up.

Even accounting for the fact that some students might have been reluctant to flag themselves in a large audience, I find this staggering, especially if these students are planning to go into basic drug discovery research. But I can’t completely blame them. I happened to take one (mandatory) thermodynamics and one (non-mandatory) basic statistical mechanics class in college and was exposed to thermodynamics in graduate school through my work on conformational equilibria and NMR. But most of my fellow graduate students in organic and biochemistry had little inkling of thermodynamics; it certainly wasn't a part of their standard intellectual toolkit.

The problem’s made worse by misunderstandings about thermodynamics that seem to linger in students’ heads even later in their career. These misunderstandings stem from a larger rift between organic and physical chemistry; the latter is supposed to be highly mathematical and abstract and rather irrelevant to the former. This is in spite of the overwhelming importance of concepts from p-chem in classical physical organic chemistry. Sadly, classical physical organic chemistry itself is disappearing from the college and grad school curriculum, and an argument in favor of emphasizing thermodynamics is also a plug for not letting physical organic chemistry become a relic of the past. No other topic gives you as good a basic feel for structure, function and reactivity in organic chemistry.

But coming back to thermodynamics, this impression that many students have about thermodynamics being all about Maxwell relations and Carnot cycles and virial theorems is rather misleading. It’s not that these things are not important, it’s just that that’s not the kind of thermodynamics Whitesides was talking about when he was talking about drug discovery. Thermodynamics in drug discovery is often much less complicated than bonafide textbook thermodynamics. And it’s of foundational importance in the field since at its core, drug discovery is about understanding molecular recognition which is completely a thermodynamic phenomenon governed by free energy.

For a drug designer, the key thermodynamic circus to understand is the interplay between G, H, and S as manifested in the classic equation ∆G = ∆H – T∆S. It’s key to get a feel for how opposing values of H and S can lead to the same value of G, since this is at the heart of protein-drug recognition. It’s also important to know the different features of water, protein and solvent that contribute to changes in these parameters. Probably the most important thermodynamic effect that drug designers need to be aware of is the hydrophobic effect. They need to know that the hydrophobic effect is largely an entropic effect arising from the release of bound waters, although as Whitesides has himself demonstrated, reality can be more complicated. But the fact is that we simply cannot understand water without thermodynamics, and we cannot understand drug action without understanding water.

Also paramount is to understand the relationship between thermodynamics and kinetics, something that again benefits from studying reactions under thermodynamic and kinetic control and things like the Curtin-Hammet principle in classical physical organic chemistry. It’s crucial to know the difference between thermodynamic and kinetic stability, especially when one is dealing with small molecule and protein conformations. Finally, it’s enormously valuable to have a feel for a few key numbers, foremost among which may be the relationship between equilibrium constant and free energy; knowing this tells you for instance that it takes only a difference of 1.8 kcal/mol of free energy between two conformers to almost completely shift the conformational equilibrium on to the side of the more stable one. And when that difference is 3 kcal/mol, the higher-energy conformation is all gone, well beyond the detection limits of techniques like NMR. Speaking of which, a good understanding of thermodynamics also tells you why it’s incorrect to rely on average NMR data to tease apart the details of multiple conformations in solution.

All this knowledge about thermodynamics is ingrained more easily than complicated mathematical derivations of configuration integrals in free-energy perturbation theory. Students need to realize that the thermodynamics that they need to tackle drug discovery is a semi-quantitative blend of ideas relying much more on a rough feel for numbers and competing entropic and enthalpic effects. This kind of feel can lead to some very useful insights, for instance regarding relationships between G, H and S in the evolution of new drugs.

It’s time to incorporate this more general thermodynamics outlook in drug discovery classes and even in regular chemistry classes. It’s simple enough to be taught to undergraduates and bypasses the more sophisticated and intimidating ideas of statistical mechanics.

In yesterday’s conference, the chairman had the last laugh. Half-jokingly he emphasized that Northeastern’s chemistry course is ACS certified, which means that one semester of p-chem and thermodynamics are mandatory. Apparently Harvard’s is not. To which Whitesides replied that he can guarantee that you will find students at Harvard who are also not familiar with thermodynamics.

Whitesides's appeal to give pharmaceutical scientists-in-training a firm grounding in thermodynamics applies across the board. On top of Plato’s Academy there was rumored to be a sign which said “Let no one ignorant of geometry enter”. Perhaps one can make a similar case for thermodynamics in the pharmaceutical industry?

Note: 

I have often written about thermodynamics in drug design on my blog. A few potentially useful posts:

1. The strange case of enthalpy-entropy compensation.

2. The unbearable heat capacity of being.

3. A drug design class act.

4. Overturning hydrophobic assumptions.

5. ∆G, ∆G†† and All That: Implications for NMR.

Some useful references:

Ken Dill - Molecular Driving Forces

Jack Dunitz - Win some, lose some: Enthalpy-entropy compensation in weak intermolecular interactions (PDF).

Ken Dill - Dominant forces in protein folding.

George Whitesides - Designing ligands to bind tightly to proteins (book chapter PDF): Includes much of the material from Whitesides's talk.
Jonathan Chaires - Calorimetry and Thermodynamics in Drug Design.