Re: AMBER: MM-PBSA and first solvation shell

From: Thomas Cheatham <>
Date: Mon, 5 Jun 2006 11:23:58 -0600 (Mountain Daylight Time)

> In the nice article "Free Energy Calculation for
> Theophylline Binding to an RNA Aptamer:
> (1):16-34. is discussed the possibility that the
> lack of quantitative agreement in the MM-PBSA
> free energy estimation can result from a
> inadequate treatment of the
> first-solvation-shell.

A paper by Spackova et al. ("MD simualtions and thermodynamic analysis of
DNA-drug complexes...", JACS 125, 1759-1769 (2003)) and its supplementary
material discuss the inclusion of the first solvation shell of explicit
water into a MM-PBSA calculation. It is argued that this provides a more
representative set of (free) energetic estimates. However, there are key
issues related to how to choose which waters to include (and how many), to
which state the waters should be associated (i.e. you need to make sure
there is a thermodynamic cycles so you do not double count; so should the
water be associated with bound and free drug or bound and free receptor?),
and how to estimate the changes in configurational entropy.

Alternatively, linear response may be explored, looking specifically at
estimates of the solvation components as 1/2 the solute-solvent
interaction energy averaged over the trajectory. A specific reference
utilizing this in the context of MM-PBSA does not spring to my mind...


\-/ Thomas E. Cheatham, III (Assistant Professor) College of Pharmacy
-/- Departments of Med. Chem. and of Pharmaceutics and Pharm. Chem.
/-\ Adjunct Asst Prof of Bioeng.; Center for High Performance Computing
\-/ University of Utah, 30 S 2000 E, SH 201, Salt Lake City, UT 84112
/-\ (801) 587-9652; FAX: (801) 585-9119
\-/ BPRP295A

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Received on Wed Jun 07 2006 - 06:07:09 PDT
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