Subject: Re: CCL: W:Solvation free energy for aromatic hydrocarbon

From: "David F. Green" <dfgreen !! mit.edu>
Date: Thu, 07 Jul 2005 20:28:49 -0400

Aromatic systems are weakly polar.  Certainly, compared to other groups 
in proteins --- hydroxyls, amides, carboxylic acids, amines and so on 
--- they are relatively hydrophobic.  However, they are significantly 
more polar than aliphatic hydrocarbons.  As you pointed out, this is 
borne out by the free energies of hydration, as well as by theoretical 
studies.  However, the interior of a protein is a vacuum, and is not 
even entirely hydrophobic (at minimum, there are buried back-bone 
amides).  Looking at transfer between water and octanol (a moderately 
non-polar enviroment), benzene falls out somwhere between propane and 
butane --- certainly preferring the more hydrophobic environment.  This 
all works out as a result of the balancing of enthalpic (both 
electrostatic and van der Waals, in molecular mechanics' terms) 
interactions between the solute and solvent and entropic terms resulting 
> from solvent structure.  More statistical frameworks (like 
hydrophobicity scales and the like)  are really just capturing the same 
underlying physics, which is why you'll often here people refering to 
them in the same language (e.g. the hydrophobic effect).

To give a quick example of how the vacuum to water transfer free energy 
may be negative, while the hydrophobic solvent to water transfer energy 
may be positive, just think about van der Waals interactions; there are 
none in vacuum, and plenty between an aromatic system in hydrophobic 
solvent.  The weak dielectric response of hydrophobic solvents (around 2 
at the very minimum) gives an added bonus, and as always, entropy is a 
hard one to deal with perfectly.

But in a nutshell, aromatic certainly do have favorable hydration free 
energies despite generally considered "hydrophobic".  It's not a 
misnomer, but more a difference in reference state.  Of course, every 
thing is always a little more complicated than what anyone tells you, 
but that's what makes it all fun.

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| David F. Green                           |                         |
| Postdoctoral Associate                   | Office: 617-253-5438    |
| Division of Bioengineering and Computer  | Mobile: 617-953-3922    |
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Chemical, , Bond wrote:
> Hi there,
> 
> I am confused with a single concept: what should be the sign for the solvation  free energy for a fragment like phenyl?  
> 
> There are many experimental data of solvation free energy for aromatic hydrocarbons, such as benzene, naphthalene, etc, but they are all negative surprisingly.  I looked at several papers with models of solvation energy, and their predictions all all have negative solvation energies for those compounds, just like the experiments.
> 
> Typically when a phenyl group is transfered from water into protein, we would like to say there is a negative(beneficial) desolvation energy, or the usual called hydrophobic effect.  And this has been used in tons of models for protein simulation or protein-ligand binding.  Note, in this context, the solvation energy (from gas into water) is positive! 
> 
> Is there something wrong over here?  Or just some artifact from the fitting?
> 
> Hope there would be some good comments.
> 
> Thanks a lot,
> Bond
> 
> 
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