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Derek Lowe The 2002 Model

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Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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« Time to Refill Your Prescription For Zxygjfb | Main | Asking the Hard Questions »

January 28, 2013

The Hydrophobic Effect: I Don't Understand It, Either

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Posted by Derek

We medicinal chemists talk a good game when it comes to the the hydrophobic effect. It's the way that non-water-soluble molecules (or parts of molecules) like to associate with each other, right? Sure thing. And it works because of. . .well, van der Waals forces. Or displacement of water molecules from protein surfaces. Or entropic effects. Or all of those, plus some other stuff that, um, complicated to explain. Something like that.

Here's a paper in Angewandte Chemie that really bears down on the topic. The authors study the binding of simple ligands to thermolysin, a well-worked-out system for which very high-resolution X-ray structures are available. And what they find is, well, that things really are complicated to explain:

In summary, there are no universally valid reasons why the hydrophobic effect should be predominantly “entropic” or “enthalpic”; small structural changes in the binding features of water molecules on the molecular level determine whether hydrophobic binding is enthalpically or entropically driven.

Admittedly, this study reaches the limits of experimental accuracy accomplishable in contemporary protein–ligand structural work. . .Surprising pairwise systematic changes in the thermodynamic data are experienced for complexes of related ligands, and they are convincingly well reflected by the structural properties. The present study unravels small but important details. Computational methods simulate molecular properties at the atomic level, and are usually determined by the summation of many small details. However, details such as those observed here are usually not regarded by these computational methods as relevant, simply because we are not fully aware of their importance for protein–ligand binding, structure–activity relationships, and rational drug design in general. . .

I think that there are a lot of things in this area of which we're not fully aware. There are many others that we treat as unified phenomena, because we've given them names that make us imagine that they are. The hydrophobic effect is definitely one of these - George Whitesides is right when he says that there are many of them. But when all of these effects, on closer inspection, break down into tiny, shifting, tricky arrays of conflicting components, can you blame us for simplifying?

Comments (14) + TrackBacks (0) | Category: "Me Too" Drugs | Chemical News | In Silico


1. Fred on January 28, 2013 12:18 PM writes...

"hydrophobic effects add up quick" a professor of mine would say. london forces are nondirectional induced if things are close the electons accomodate...and add up to create a strong bond.

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2. JRnonchemist on January 28, 2013 12:23 PM writes...

My understanding was that the Rabies virus infects the nervous system, and for some reason makes it painful to drink water.

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3. Am I Lloyd peptide on January 28, 2013 12:27 PM writes...

@2: "Hydrophobic" threw you off, didn't it?

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4. Pete on January 28, 2013 1:19 PM writes...

One factor that studies like these tend not to take account of is how the characteristics of one hydrogen bond affect the characteristics of other hydrogen bonds. For example if water donates one hydrogen bond if is less able to donate another (although it becomes a better HB acceptor). Whether you call it co-operativity or polarisation, this behaviour will depend on the geometry of the water network.

The authors state "The entropic profile is related to changes in the degree of ordering and the dynamic properties of the water molecules..." and I'm not sure that one should be talking about dynamic properties in this context. Entropy can be thought of as being determined by the shapes of potentially energy surfaces. We can sample these PE surfaces using molecular dynamics but we can also use Monte Carlo.

I believe that one characteristic of the hydrophobic effect that makes it difficult to model is that it is non-local in nature.

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5. Wile E Coyote, Genius on January 28, 2013 1:20 PM writes...

@2: Rabies virus paralyzes the throat, so that animals (or infected people) can't swallow. Therefore the foaming of the mouth (can't swallow saliva) and the "fear" of water. I don't think that the "hydraphobie" from the Old Yeller movie has much to do with the chemistry being discussed.

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6. luysii on January 28, 2013 6:26 PM writes...

"Water is so familiar, we generally consider it to be a rather bland fluid of simple character. It is, however, a chemically reactive liquid with such extraordinary physical properties that, if chemists had discovered it in recent times, it would undoubtedly have been classified as an exotic substance."

Vogt and Vogt -- Biochemistry 3rd edition p. 39

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7. JRnonchemist on January 28, 2013 7:08 PM writes...

I figured it was the obvious joke, and had to make it.

More seriously, it looks from what everyone is saying that this is like cancer, a bunch of different mechanisms bundled together with the same name because it seems to make sense that way.

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8. Bobby Shaftoe on January 28, 2013 7:47 PM writes...

Along similar lines, I hear "pi-pi stacking" bandied about all the time, for example to rationalize interactions present in a crystal structure. If this effect is indeed real, it is certainly counterintuitive. Phenyl groups are quadrupoles: their charge is distributed much like a dz2 orbital where negative polarization is on the faces and positive polarization resides on the side of the ring. Why should two like-charged faces attract?

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9. Curious Wavefunction on January 28, 2013 10:25 PM writes...

@8: There's a lot of fascinating work done on pi stacking recently. The most preferred arrangement for pi stacking is actually T-shaped where one ring approaches the other head on. Recent work by Ken Houk and others also suggests that the attraction is between the substituents rather than the rings.

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10. Cytirrps on January 29, 2013 10:23 AM writes...

Poor choice to pick thermolysin, which has a metal ion in the binding pocket, for studying hydrophobic effect. Just think about the hydration shells around the metal ion.

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11. dearieme on January 29, 2013 7:46 PM writes...

The study of chemistry gets a lot easier when you realise that large chunks of the discourse involve labels and metaphors rather than the sort of explanations a physicist would hope for. Hell, it's complicated.

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12. dearieme on January 30, 2013 4:11 AM writes...

The study of chemistry gets a lot easier when you realise that large chunks of the discourse involve labels and metaphors rather than the sort of explanations a physicist would hope for. Hell, it's complicated.

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13. gobblydegook on January 30, 2013 10:52 AM writes...

Seriously? Usually the posts/discussion here are pretty reasonable. This paper is awful. This discussion is awful.

Lots of people understand the hydrophobic effect. Even Schrodinger (the software company, not the man) now claims to understand it in terms of happy waters and sad waters, but only if you pay them lots of money.

You shouldn't be able to write papers where you misuse about every term ever, but you still are. I guess those are the perks of being a famous professor.


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14. hansp on November 5, 2013 4:16 AM writes...

A matter that I have never seen addressed is
the non-linearity of the water molecule.

Why don't the atoms in water arrange themselves in
a straight line, as a simple distribution
of electrical charges would demand? --When posing
this question I always get showered (!) with
Lewis pairs, sp-hybrids and the manifold wonders
of hydrogen bonds and all the wonderful things they do for us, but the `why' is sorely wanting.

Could you shed some light on this?

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