Field of Science

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:


Some useful references:

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.

26 comments:

  1. "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."

    Unfortunately, most PChem books - and, thefore, PChem instructors - pay an inordinate amount of attention to these concepts.

    Dill's book is one of the few exceptions but I am not sure how widely used it is. I use it for one of my courses, and have blogged about some of the some of the gold nuggets here.

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    1. Thanks for the link. Dill is great although it's a serious book. Interestingly, I personally have learnt many useful drug-discovery related thermodynamics concepts from the literature rather than from books. An example would be the Dill review on protein folding which has great sections on the hydrophobic effect.

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    2. Since in many Chem programs around the world the students are introduce to thermodynamics in a very early stage, where the Carnot cycles and Maxwell relationships are fundamental, they get scare by this non easily tangible ideas. I strongly agree that a big problem is the lack of courses like physical organic chemistry, where this concepts are more intuitive to the student. Nevertheless, many Universities think that the concepts related to this branch are smoothly introduce in other courses. And the big problem is now the context where this ideas are presented. Mostly like facts that you should already know rather than a new concept.Using a Book like Dill's Molecular driving forces in an early stage is going to be scarier, because the students doesn't have the ground and the mathematical toolbox to fully understand the statistical scope.

      I believe that the possible reason to why people like Wavefunction prefer to learn from peer review articles rather than books is because the thermodynamical approach in chemistry related process is still in early stage. This could be due to the quantum revolution that many researchers preferred to use quantum mechanical approaches instead to the thermodynamical one. Other reason is that thermodynamics is very tricky like Ben-Naim show here:

      http://pubs.acs.org/doi/abs/10.1021/ed2002708

      Despite all of this, I believe that drug design is the first clear application of thermodynamics and this will attract the attention of the universities Chem curriculums,

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  2. This is staggering.

    OK, I guess some people in a drug design conference are going to have come through more biochem routes, but for anyone with a bachelors or masters chemistry degree not to have even a basic idea of the thermodynamics of equilibrium and spontaneity of reactions is surely some kind of joke? Perhaps, as you suggest, these people don't associate those things with 'thermodynamics' per se...

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    1. Yes, I think that's what happens. People get bored with the thermodynamics that they do learn in p-chem because most traditional courses in the subject don't relate the concepts semi-quantitatively to things like drug design. This creates the impression that thermo is just another mandatory obstacle on the road to a degree. We need something of the equivalent of The Feynman Lectures on Physics for thermodynamics.

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  3. I am aghast. Completely aghast.

    C.P. Snow once compared ignorance of the 2nd law of thermo to not having read Shakespeare. I guess we won't have to worry about the 2 cultures anymore, huh?

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    1. Indeed. The cliche about the two cultures is a cliche because it's true. I increasingly believe that our educational system has failed in driving home the importance of thermodynamics for pharmacology, drug discovery and biology in general.

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  4. "These misunderstandings stem from a larger rift between organic and physical chemistry...."

    My anecdotal observation is that this rift likely is between certain subfields of organic chemistry and physical chemistry - I've met plenty of inorganic chemists happy to conduct/collaborate on computational/physical studies, as well as the more materials/polymer-focused organic chemists.

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    1. True, I was thinking more of the rift between organic and physical chemistry in college and grad school which is often caused by ignoring the bridge between the two built by physical organic chemistry. If you are taking a class in physical organic chemistry you inevitably appreciate thermodynamics. Not so much if your organic classes mostly consist of synthesis and spectroscopy.

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    2. Point taken. I suppose I might not have seen the worst of it, as my graduate alma mater did have a decent core of physical/materials/mechanistic organic chemists, and they - and their students - seemed to be fairly comfortable with thermodynamics.

      In terms of constructive suggestions - what about instituting graduate core curricula in chemistry departments? I know a few are doing so, and I know this sort of approach is very popular with various integrative/interdisciplinary bioscience programs. Also, if one thinks about it, this is essentially what happens in physics departments in the US - everyone, whether putative theorist or aspiring experimentalist, has to take so much classical mechanics, electrodynamics, QM, and stat mech no matter their intended area of research.

      As a final note - can't remember if I've previously shared this with you, or if you've already seen it, but I really like this review - www.rpgroup.caltech.edu/publications/Garcia2011a.pdf - on the "unreasonable effectiveness of...thermodynamics and statistical mechanics in biology."

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    3. Thanks for the link, looks interesting. I think you make a very good point about core requirements that everyone has to take, irrespective of their major and future plans. I remember reading that that's one of the things that makes the undergraduate program at Caltech stand out from others. You are also right that physics departments seem to have more widely implemented these core requirements.

      I think part of the problem is a proliferation of electives that sometimes keeps students from having both the time and inclination to appreciate the importance of a core education. I think we have been a little too liberal with this idea of flexibility that allows everyone to take whatever classes they want with total freedom. A colleague of mine whose daughter is studying evolutionary biology at Princeton told me that she isn't required to study organic or physical chemistry or even cell biology. I see a problem.

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    4. The United States Naval Academy takes the Caltech idea one step furthur: It has a common core science curriculum for ALL majors (even English).

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  5. And chemical kinetics???????

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    1. Also important, but when you are mostly looking at interactions between drug and protein, I think thermodynamics matters much more. Of course there's things like off rates which are important in mediating interactions; I blogged about this a while back: http://tinyurl.com/98hgvkw

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  6. Interesting problem here... .one I did not experience. Even though I focused on organic chem in grad school I was required to take a 700 level class in thermodynamics. It was the hardest class I ever took. I joke that it was a class all about why PV does not really equal nRT. (There was a lot more to it than that but my students can relate with this equation.) Then I took a 500 level physical organic class that was focused on thermodynamics. So I did not experience what you are talking about here. I graduated in 2002.

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    1. Wait, PV is *not* equal to nRT? Kidding of course, I think it's worth knowing the subtleties. You clearly seem to have struggled through the meat of the class but a lot of people get discouraged and don't want anything to do with it later. Part of my argument is that this is tragic since they don't need all that complicated stuff for understanding drug action. I think thermodynamics suffers from being a very old and classical subject and needs to be revised to reflect the needs of biology/biochemistry students who are going into fields like drug discovery.

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  7. "It’s simple enough to be taught to undergraduates and bypasses the more sophisticated and intimidating ideas of statistical mechanics." - Don't you think those are important (and interesting) in their own right?

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    1. Yes, they are. But you can mostly get away without knowing much of them if you want a *qualitative* understanding of the thermodynamics of protein-drug interaction. Anything deeper and you definitely want to understand free-energy perturbation theory from statistical mech.

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  8. I think part of the problem stems from a reduction in the significance of graduate coursework in favor of research. Classes in grad school are practically meaningless hurdles that only weed out those not willing to put in a trivial amount of work.

    If you look at the best organic chemists, they have an understanding of both the synthetic and the thermodynamic aspects of their work. The older cohort of organic chemists that are now approaching the end of their careers was forced to take (and be proficient in) rigorous thermodynamic coursework even without having courses relating it to drug discovery and synthetic methodology.

    Perish the thought that we should ask graduate students to be mature enough to take courses in subfields of chemistry not directly relevant to their subfield and expect them to learn the material.

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    1. True. The old guard matured during the heyday of physical organic chemistry and MO theory so they are familiar with these fields. In this sense our curriculum has regressed. I don't know what the solution is except to make the material simpler and more relevant to daily life.

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    2. Well, in my opinion, the solution is to start failing/kicking some students out of grad school. Not doing so has contributed (significantly) to the proliferation of PhDs and our current employment problem.

      Many students I was in grad school with got a PhD for "putting in the time", something that provides low quality PhDs who cannot adapt to new fields with changes in the job market, and contributes to watering down of the market and making the degrees of strong students worth less (but of course not worthless). Some of this has to do with the oft discussed nature of academia (tenure and funding) but it also has to do with the ethics of the professors and institutions. Anything for funding, more papers, higher graduation rates leads to the mess we're in now.

      Getting a PhD should be a challenge, no matter how much you want it, how much work you do, some people should be told "You aren't going to get a PhD." Something very rare these days.

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    3. Yes, I agree. But I will lay the blame for the declining standards of PhDs mainly at the feet of the the publish-or-perish culture and the entrenched ambitions of academics. The problem is that many professors are perfectly happy to have non-thinkers work for them 80 hours a week and then give these glorified technicians PhDs simply for providing cheap labor. Very few want to reward independent thinking, creative cross-fertilization of ideas and risk-taking. As you said, these days PhDs can be awarded for simply putting in the time and this has definitely led to a cheapening of the system. Something like what's happened to MBAs.

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  9. OK. Here's my 2c on this. My opinion is that thermo and kinetics should be covered in a very serious manner in Gen Chem II. That includes, I think, what Whitesides is implying might be important for drug discovery. If you cover thermo and kinetics correctly in GCII, you can have serious conversations about pH and pKa for all those pre-med majors who need this stuff. Now ... if students get a very solid and very firm foundation for thermo and kinetics in Gen Chem II, that opens up the rest of your curriculum to do all sorts of things. If you don't have to revisit any of this in PChem (get straight to probabilities and quantum and intricacies), Inorganic (advanced acid-base chemistry and functional electrochemistry), biochemistry (get started right on data plotting schemes and analysis) you can cover a lot more interesting things.

    I have said before that the second semester of Gen Chem and the second semester of Organic should be the most important classes that chem majors take. I think that if professors believe this and act on it, they can get to be very creative/innovative with the curriculum for their junior and senior majors.

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    1. The inorganic course you describe seems to me to actually be an analytical chemistry course. Those are topics I covered in my analytical classes as both an undergrad and grad student. Modern inorganic (an advanced inorganic junior/senior level course) in my view should be a course on advanced bonding theory and applying that theory to organic (organometallics), biochem (bioinorganic), and materials.

      As far as important courses, as a synthetic inorganic/organometallic chemist, I think that the p chem sequence is the most important for the undergrad theory-wise (and I prefer the quantum-stats-thermo sequence of topics). Organic and analytical are most important for lab/practical skill development.

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  10. I teach thermo and kinetics to 140 life science students and I finally think I am getting through. Part of this is that I skip stuff like Maxwell relations and proofs, like the Clausius inequality and focus on visualization.

    For this I use my text book which is not for life science students but they seem to like it: Physical Chemistry by Laidler, Meiser and Sanctuary. It is an ebook too and the thermo module costs $14.99 http://bit.ly/UIBxtc(the hard copy costs $150!). However I can use the multimedia clips in the book--just pop them up in class. So they can see a reversible and irreversible process; they can roll 10 dice and see the randomness of entropy; or go through the steps of a calorimetry experiment. Some are shown here taken from my course: http://bit.ly/RgBs0L

    I want to leave to students with a view that will stay with them. I also want them to "read" equations like a story, and I tell them they do not have to reproduce a derivation, only understand it.

    I try to make physical chemistry interesting and stress that it plays a huge role into any branch of science. This has been easier using animations in class.

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    1. You certainly seem to be doing things the right way. I am glad to hear that you collaborated with Keith Laidler and will definitely check out the book. I love Laidler's work, both his textbooks on kinetics and his popular books on the history of science.

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