Are you using linear or non-linear PB? Given the protocol you describe, the values based on a single trajectory are probably not reasonable .... In my experience with protein-DNA, a protocol with nonlinear PB, internal dielectric >= 4 is crucial. Besides, INP=1 may give good trends but we dont get anywhere close to the reasonable values we get with INP=2 ... Again this is based on protein-DNA binding, things may be different with intercalating drugs.
Our basic protocol for protein-DNA is described here
http://www.cell.com/structure/abstract/S0969-2126(14)00206-8
We do see that more independent simulations greatly help improve the convergence of the calculations (each of which reasonably long though). We are preparing a manuscript with lots of details on how different parameters influence MMPBSA results for protein-DNA but it will take probably a couple of months until publication
Hope this helps
Vlad
On September 21, 2014 11:51:16 AM CEST, 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.
>
>I'd welcome suggestions, or advice if this set-up is just unsuitable
>for post-processing. I'd particularly like to get a decent handle on
>entropic nmode values, which appear pretty consistent between 1-traj
>and 3-traj.
>
>Gratefully,
>
>Keiran
>
>
>#### 1 TRAJECTORY RESULTS ###
>Differences (Complex - Receptor - Ligand):
>Energy Component Average Std. Dev. Std. Err.
>of Mean
>-------------------------------------------------------------------------------
>VDWAALS -69.6674 2.3792
>0.1682
>EEL -1107.9129 8.2627
>0.5843
>EPB 1125.6907 8.5577
>0.6051
>ENPOLAR -5.2310 0.0845
>0.0060
>EDISPER 0.0000 0.0000
>0.0000
>
>DELTA G gas -1177.5803 9.1659
>0.6481
>DELTA G solv 1120.4597 8.5326
>0.6033
>
>DELTA TOTAL -57.1206 2.6501
>0.1874
>
>
>-------------------------------------------------------------------------------
>-------------------------------------------------------------------------------
>Using Normal Mode Entropy Approximation: DELTA G binding = -36.0906
>+/- 2.7370
>-------------------------------------------------------------------------------
>-------------------------------------------------------------------------------
>
>### 3 TRAJECTORY RESULTS ###
>Differences (Complex - Receptor - Ligand):
>Energy Component Average Std. Dev. Std. Err.
>of Mean
>-------------------------------------------------------------------------------
>BOND 8.3128 18.1988
>1.2869
>ANGLE 19.2670 21.9093
>1.5492
>DIHED 3.9187 14.0373
>0.9926
>VDWAALS -34.4527 11.9431
>0.8445
>EEL -1479.7979 44.3041
>3.1328
>1-4 VDW 1.5640 8.7540
>0.6190
>1-4 EEL 5.0865 23.8725
>1.6880
>EPB 1474.1219 37.9096
>2.6806
>ENPOLAR -3.4303 0.2760
>0.0195
>EDISPER 0.0000 0.0000
>0.0000
>
>DELTA G gas -1476.1016 50.3651
>3.5614
>DELTA G solv 1470.6916 38.0114
>2.6878
>
>DELTA TOTAL -5.4100 28.7193
>2.0308
>
>
>-------------------------------------------------------------------------------
>-------------------------------------------------------------------------------
>Using Normal Mode Entropy Approximation: DELTA G binding = 18.1623
>+/- 28.7635
>-------------------------------------------------------------------------------
>-------------------------------------------------------------------------------
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Received on Sun Sep 21 2014 - 04:00:02 PDT
