Subject: Re: CCL:pKa calculation

From: [email-masked] (Per-Ola Norrby)
Date: Tue, 26 Nov 1996 09:16:43 +0100

Hi Alex,

>Whilst what you are saying is very interesting as far as it goes, it takes
>no account of the entropic change on solvation.

        Well, it does!  Some continuum solvation models (like the
Cramer-Truhlar models) calculate solvation free energies.  It's true that
many ab initio-based models only calculate the electrostatic contribution,
and for an isodesmic comparison that may actually be enough, but the SMx
models do give free energies of solvation.  Combining those with a normal
mode analysis for the remaining thermodynamic contributions should be a
very cost-effective way of getting the overall equilibrium free energies.

>The only method of which I am aware that will do this would be QM/MM
>FEPT. This can be done at all levels of ab-initio theory - if you have a
>big enough computer!  Hoever - I am begining to believe that it will give
>reasonable results at AM1 level - and thus be do-able for small systems
>- on a work-station.

        I'm very interested in QM/MM methods, but if you use them for FEP,
can you calculate any practical systems (say, 10-15 heavy atoms + a couple
of hundred water) this millenium, on ANY computer?  Also, FEP is only
theoretically defensible if you have a good description of the potential
energy surface at low energy non-stationary points, and we all know that
AM1 will give substantial errors even for relative energies of stationary
points.  Of course, as long as it works and gives good results, I wont
insist on a perfect theoretical background, but I'd like to see comparison
to experiment for a couple of hundred cases first.

        Regards,

        Per-Ola Norrby

^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
 *  Per-Ola Norrby
 *  The Royal Danish School of Pharmacy, Dept. of Med. Chem.
 *  Universitetsparken 2, DK 2100 Copenhagen, Denmark
 *  tel. +45-35376777-506, +45-35370850    fax +45-35372209
 *  Internet: [email-masked], http://compchem.dfh.dk/

---

From: Christopher J Cramer <[email-masked]>
Date: Tue, 26 Nov 1996 09:59:01 -0600 (CST)

A small point of clarification on this thread:
> models do give free energies of solvation.  
> 
   Even the electrostatic component of solvation as calculated by most
continuum models formally has the status of a free energy (it's just not ALL
of the free energy of solvation). That is because one usually invokes linear 
response theory to account for the "cost" of solvent distortion in order to 
solvate the solute, and that includes both enthalpic and entropic terms. So, 
the Born formula, the Onsager formula, etc., all calculate free energies.
Several studies on the validity of linear response theory have appeared, and
the consensus seems to be that it works fine for solutes that do not
concentrate large amounts of charge over very small volumes (e.g., singly
charged atoms are OK, but doubly and higher charged atoms are not).
Naturally, however, there are some dissenters. In any case, SCRF models
almost always use a Hamiltonian that includes the cost of solvent distortion
and build a Fock operator to minimize the expectation value for that
Hamiltonian, the result then being a mixture of potential energy (from the
usual components of the Fock operator) and free energy (from the
solute/solvent mutual polarization).

   As for the rest of the free energy of solvation, the SMx models, and
modifications of other continuum models like Rivail/Rinaldi, Tomasi's PCM, 
COSMO, etc., typically assume a proportionality between this quantity and 
molecular surface area and by parameterization against experiment they 
predict the full free energy of solvation -- THE ONLY PHYSICAL OBSERVABLE 
since the components are not measureable with the possible exception of very 
special systems where certain components must be zero. More complicated 
approaches to estimating dispersion, cavitation, etc. have been proposed, but 
in the absence of these properties being experimentally accessible, it is 
difficult to decide whether they are worth the extra effort (opinions on 
this subject vary).

Chris
-- 

Christopher J. Cramer
University of Minnesota
Department of Chemistry
207 Pleasant St. SE
Minneapolis, MN 55455-0431
--------------------------
Phone:  (612) 624-0859 || FAX:  (612) 626-7541
[email-masked]
http://pollux.chem.umn.edu/~cramer