[gmx-users] Is the PMF from "gmx wham" a free energy curve?

[Justin Lemkul]

On 1/5/15 8:52 AM, Alexander Björling wrote:
> Dear users,
>
> I have a question about how to interpret (rather than about how to perform)
> a GROMACS calculation.
>
> I have calculated the Potential of Mean Force for separating two protein
> chains, in order to estimate the free energy of monomerization for this
> dimer, loosely following Justin Lemkul's tutorial. I have arrived at a PMF
> which seems reasonable and robust according to the error estimates of "gmx
> wham". The reaction coordinate is the distance in the Z-direction only,
> nothing is position restrained, and there is good overlap between the 2 ns
> windows.
>
> My question: is the resulting PMF a correct estimate of the free energy of
> monomerization, or are there missing entropic terms due to the
> translational confinement?
>
> Google turns up a JACS paper (dx.doi.org/10.1021/ja2060066), claiming that
> the missing entropy is as large as 15-30 kcal/mol, which seems very high to
> me:
>
> "The PMF is expected to decrease after the monomers are completely
> dissociated because of the gain in translational and rotational entropy.
> According to previous reports, this entropy gain is anticipated to be on
> the order of 50-100 cal/(mol K). Thus at 300 K the PMF is expected to
> decrease 15-30 kcal/mol upon dissociation."
>
> Is this true?
>

Certainly plausible.  The output of gmx wham is indeed a free energy profile per 
the WHAM algorithm that is used ubiquitously.  Does it necessarily tell the 
whole story?  Not necessarily; but the entropy term is almost certainly system 
size-dependent.  I haven't read the JACS article, but dissociation of a protein 
dimer probably has a large entropy term.  For smaller peptides or protein-ligand 
complexes, the effect is likely far smaller.

-Justin

-- 
==================================================

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalemkul at outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

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