Re: [AMBER] Suitability of MMPBSA to intercalator binding. 3-trajectory no improvement over 1-trajectory?

From: Jason Swails <jason.swails.gmail.com>
Date: Sun, 21 Sep 2014 09:42:09 -0400

On Sep 21, 2014, at 5:51 AM, Keiran Rowell <k.rowell.unsw.edu.au> wrote:

> Dear Amber list,
>
> I'm trying to use MMPBSA to get some sort of qualitative trends in binding energies of a range of intercalators (molecules which insert between DNA bases).
>
> So far I've been using PB (inp=1, radiopt=0 because of new parameters) + nmode (nmode_igb=1) 1-trajectory MMPBSA, with the DNA as the receptor and my drug as the ligand. This gives an okay dG (~ -25 to -40) but little in terms of discernible trends. I thought 3-trajectory might be an improvement since there's significant structural changes to the DNA upon intercalation (not your 'lock and key' type receptor) so I thought getting separate 'receptor' values from unintercalated DNA might be more prudent.
>
> However upon doing this I get positive dG values and large std. dev.s, something like 20 +/- 30. I know structural values won't perfectly cancel with 3-traj, but the drop in VANDW also seems significant considering stacking interactions are what stabilise intercalated complexes. I've put an example difference output of 3-traj and 1-traj at the end of this message.
>
> I should note a few things which might interfere with getting good results aside from unusual 'ligand/receptor' definitions. One is my intercalators have +2 charge and so when I run the DNA on its own I have 2 extra Na+ atoms to make sure the receptor system is neutralised, but make sure to strip all solvent from the trajectories being processed. My intercalators are also dimeric so likely have a process of two insertions occurring an separate times, whereas my MD is starting from the complexed structure due to time constraints.

Vlad gave a great response, so Iíll just make some other comments. Do not add these ions. There are some instances where a net neutral state is desirable (i.e., in some periodic simulations), but this is certainly not one of them. If you think about the thermodynamic cycle that defines MM/PBSA, you will have a tough time justifying the addition of those two ions ;).

In my opinion, you should omit _all_ ions from your system (unless they are structurally relevant) and look into the non-linear PB equation to improve the treatment of the highly-charged system.

HTH,
Jason

--
Jason M. Swails
BioMaPS,
Rutgers University
Postdoctoral Researcher
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Received on Sun Sep 21 2014 - 07:00:02 PDT
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