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 - 03:00:02 PDT
