AMBER Archive (2006)

Subject: Re: AMBER: MM_PBSA : Question about Stability?

From: David A. Case (case_at_scripps.edu)
Date: Wed Aug 16 2006 - 11:24:48 CDT

On Wed, Aug 16, 2006, Guillaume Bollot wrote:

> I have a macromolecule which contain 32 lysines. I changed manually the
> protonation state of the lysines (ex: 50% protonated lysine and 50% neutral
> lysines). I already performed molecular dynamic in vacuo for each
> arrangement (100%LYN; 25%LYN-75%LYS; etc...). After that, I would like to
> know the relative stability for each arrangement with MM_PBSA.PL. My
> questions are :
>
> 1- Could I use GBTOT in mm_pbsa log file to know the stability?
> 2- GBTOT represent the Absolute Free Energy?
> 3- Is my methodology correct?
>

If I understand correctly, your methodology is not correct.

Molecular mechanics energies are relative to an arbitrary "zero" of energy and
have no intrinsic meaning in themselves. For example, the energy of a bond is
set to zero (by convention) at its equilibrium length. Hence the strength of
the chemical bond is not represented in any way in its energy: strong and weak
bonds are both zero at their equilibrium values.

You can compare the relative energies of two conformations of the same system,
since they share a common zero of energy. But you cannot compare the energies
of two systems that have different numbers of covalent bonds. And you
certainly cannot compare the energies of systems with different numbers of
atoms.

The way to make such comparisons is to construct thermodynamic cycles and
compute delta-delta-E (or G), so that the arbitrary zero of energy can cancel
on two sides of such a cycle. You problem sounds a lot like a "gas-phase pKa"
(or proton affinity) calculation: study the way such calculations are done in
condensed phase, and see if some similar cycle might meet your needs.

...good luck...dac
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