Subject: Re: CCL:implicit solvation

From: "Peter Shenkin" <[email-masked]>
Date: Fri, 7 Oct 1994 11:25:51 -0400

On Oct 6,  9:58am, Tony Schmidt wrote:
> >Conclusion of the summary was:
>
> >> Finally, when using the "Eisenberg" approach of surface area changes and
> >> atomic solvation parameters:
> >>
> >>        1) It is currently unclear as to what is the most appropriate
> >>           set of atomic solvation parameters to use for docking
> >>           or protein folding.
> >>
> >>        2) Given the potential benefits of such a calculation there
> >>           seem to be surprisingly few tests of this method.
> ...
> The paper "A CFF91-based continuum solvation model: solvation free energies
> of small molecules and conformations of the alanine dipeptide in solution"
> by A.B.Schmidt and R.M.Fine to be published in Molecular Simulation, 1994.
>
> In particular, we have shown that the Wesson-Eisenberg model used in [7]
> provides the differences in the solvation energies of the alanine dipeptide
> within the full Ramachandran map not exceeding 4 kcal/mol while the
> Poisson-Boltzmann approach exhibits the difference between C7 axial and
> alpha L minima of about 9 kcal/mol (not to mention energy maxima).

I don't quite follow you.  Are you saying that W-E gets things right
to +/- 4 kcal/mol whereas P-B gets things right to only +/- 9 kcal/mol?
If this isn't what you're saying, what are you saying?  I'd have expected
P-B to do better than W-E.

It is interesting to try to define test cases which will exhibit
differences in rank-orderings of free-energy (including solvation)
when calculated using:

	distance-dependent dielectric
	purely surface-based methods, such as W-E
	continuum models, such as P-B, or GB/SA
	explicit solvent.

I list this in order of probable "maximum attainable quality", which
corresponds to the the order of increasing difficulty of implementation.

As an example, here is a situation which a W-E model should get
wrong, but a continuum model could get right:

                      --                      --
                     |  |                    |  |
                     |  |  Different sorts   |  |
                 B---|  |  of side-chain     |  |---A
 (charged external   |  |  packing can       |  |   (charged external
         sidechain   |  |  happen in here.   |  |   sidechain)
                     |  |                    |  |
                     |  |                    |  |
                     |  ----------------------  |
                     | (funny U-shaped protein) |
                     ----------------------------

The question is:  How do the optimal conformations of A and
B vary, according to what happens to the sidechains in the cavity?
All a surface-based solvation model does is to try to optimize the
solvent exposure of A and B with respect to their immediate local
environments.  But the dielectric shielding between A and B depends
importantly on the dielectric constant in the cavity, which, even
ignoring fluctuations, depends on how much water is in there.

The work of Gilson and Honig points out other situations which
share the same feature:  the solvation energy (and the optimal
conformation) of a charged group can depend upon what happens
in a remote location.  I believe that more recent work by Anthony
Nicholls and Marilyn Gunner shows that this can be important in
real proteins as well as in concocted models.

	-P.

-- 
*********** World music:  What bluegrass is to a Bulgarian. **********
*Peter S. Shenkin, Box 768 Havemeyer Hall, Chemistry, Columbia Univ.,*
* New York, NY  10027;     [email-masked];     (212) 854-5143  *
**** If Sammy the Bull can turn Rat, who can feel safe any more? *****

---

From: [email-masked] (Tony Schmidt)
Date: Fri, 7 Oct 94 13:01:51 -0400

------------------------------------------------------------------------
We certainly believe P-B approach is more accurate than W-E. For the 
alanine dipeptide, W-E provides rather flat Ramachandran map, i.e.the
difference between the maximum and minimum conformational energy is about
4 kcal/mol. P-B yields much more pronounced energetic profile.

Tony Schmidt
[email-masked]