Re: AMBER: GAFF + AM1BCC & small-molecule aggregation

From: Thomas E. Cheatham, III <>
Date: Wed, 1 Mar 2006 14:17:35 -0700 (Mountain Standard Time)

> I've run a Langevin dynamics simulation of a system composed of the
> protein bcl solvated in explicit water containing a number of
> adenosine-like small molecules. After a nanosecond of so of production
> dynamics the adenosine compounds have begun to aggregate into rather large
> clusters. This aggregation behavior was not expected (at least not by
> me). The adenosine molecules have been parameterized using GAFF with
> AM1-BCC partial charges, and the protein is using ff03 with TIP3 waters.

That is a beautiful picture of the aggregation. My guess is that you
would see this behavior even with a RESP charge model and likely other
force field choices as well, however that is pure speculation on my part.
I have observed such behavior in similar polyol systems (a set of rings
with lots of hydroxyl groups) and upon simulation of poly-A single
stranded DNA (all unpublished).

I seem to be missing all of my relevant references at the moment, but it
is known that free adenine bases in solution will "stack", that
poly-adenine single strands will form stacked helical structures, and that
ATP self-associates (Chattopadhyaya, Biochem 43, 15996-16010 (2004);
Gilligan & Schwarz, Biophys. Chem. 4, 55-63 (1976); Weaver & Williams,
Biochem 13, 8899-8903 (1988)). So, this behavior *may* be reasonable, or
at least is not completely unexpected. The question is, does the force
field have the proper balance between free and associated molecules.

To determine this, you will need to infer what the correct association
equilibrium constant from experiment is, and then figure out the effective
concentration in the simulation, noting that in that small periodic box
you have a relatively high adenosine-like molecule concentration.
Looking at the simulation box, I am not worried about the di-mers, however
that large clump of ~10 residues may be unrealistic, on the other hand
there are hydrophobic driving forces that support aggregation of the
methylene groups with good inter-molecular hydrogen bonding possible...

 -/ 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 Sun Mar 05 2006 - 06:10:13 PST
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