From: Lewis Martin (lewis.martin44_at_gmail.com)
Date: Thu Feb 28 2013 - 23:16:21 CST
Hi NAMD experts,
I am trying to conduct an FEP run to measure the free energy change between
a drug in solution and the drug bound in a protein. Unfortunately, at one
end of the lambda value, dG is not a smooth curve but is smooth in parts,
punctuated by sudden jumps (example below). The jumps only seem to occur
when the exnihilated (appearing) particle, i.e. the drug bound in protein,
is barely there - i.e. at low lambda values.
There is a restraint applied to both drug in bulk water and protein-bound
drug using the colvars module. This restraint holds an atom from one end of
the drug in a sphere of 6 angstrom. In water it is held to a dummy atom, in
the protein it is held to an atom with which the drug appears to hydrogen
bond. By looking at trajectories and the colvar output, it doesn't look
like this restraint is being applied when the jumps occur.
What reasons could there be for this sudden jumping in dG, and can it be
avoided altogether or just minimised? Any advice would be much appreciated.
Lewis
Relevant config parameters and results:
Config file:
colvars on
colvarsConfig colvars.in
alch on
alchType FEP
alchFile bcpitlipidfep.pdb
alchCol B
alchOutFreq 10
alchOutFile feppit.out
alchEquilSteps 250000
alchVdwLambdaEnd 1.0
alchElecLambdaStart 0.5
alchVdWShiftCoeff 5.0
alchDecouple yes
alchLambda 0.0
alchLambda2 0.05
Colvars.in:
colvarsTrajFrequency 100
colvarsRestartFrequency 10000
colvar {
name protnitrogen
width 1.2
lowerBoundary 0.0
upperboundary 16.0
lowerWall 0.0
lowerWallConstant 10.0
upperWall 3.0
upperWallConstant 5.0
distance {
group1 {
atomnumbers { 40815 }
}
group2 {
atomnumbers { 14577 }
}
}
}
colvar {
name waternitrogen
width 1.2
lowerBoundary 0.0
upperboundary 16.0
lowerWall 0.0
lowerWallConstant 10.0
upperWall 3.0
upperWallConstant 5.0
distance {
group1 {
atomnumbers { 40838 }
}
group2 {
dummyAtom { (7,28,-35) }
}
}
}
And an example of the offending dG jumps, illustrating a jump from ~14 to
~12:
# STEP Elec vdW
dE dE_avg Temp dG
# l l+dl l
l+dl E(l+dl)-E(l)
#NEW FEP WINDOW: LAMBDA SET TO 0 LAMBDA2 0.05
FepEnergy: 512860 -97721.1068 -97715.6684 -316.0235
-308.8805 12.5813 24.0799 295.8700 14.5684
FepEnergy: 512870 -97778.2827 -97773.7645 -280.8494
-272.6218 12.7458 24.0711 296.7329 14.5581
FepEnergy: 512880 -97878.9187 -97874.1597 -144.5814
-137.0659 12.2745 24.0621 297.4740 14.5428
FepEnergy: 512890 -97980.6855 -97975.7543 -42.6487
-35.6058 11.9742 24.0531 296.8308 14.5277
FepEnergy: 512900 -97812.3256 -97808.2015 -205.4871
-196.4986 13.1127 24.0442 296.2870 14.5105
FepEnergy: 512910 -98203.4208 -98198.8762 75.5507
84.7087 13.7026 24.0360 298.4239 14.5082
FepEnergy: 512920 -97957.6685 -97952.9902 -248.4170
-239.5962 13.4992 24.0281 296.6832 14.5071
FepEnergy: 512930 -97860.1500 -97856.1190 -341.7438
-334.1516 11.6232 24.0191 296.8598 14.4831
FepEnergy: 512940 -97879.8155 -97874.9483 -248.7486
-240.9590 12.6569 24.0100 295.3335 14.4610
FepEnergy: 512950 -97942.1857 -97937.6010 -147.8696
-140.6553 11.7990 24.0008 295.1580 14.4301
FepEnergy: 512960 -98078.7729 -98073.9242 -168.9979
-162.2856 11.5610 23.9912 296.1460 14.3771
FepEnergy: 512970 -97956.7627 -97952.6943 -234.0133
-227.5177 10.5640 23.9815 296.2719 14.2787
FepEnergy: 512980 -97987.5988 -97983.3314 -271.7985
-265.4929 10.5730 23.9711 295.1019 14.0694
FepEnergy: 512990 -97824.2914 -97819.2752 -329.2782
-324.2448 10.0496 23.9608 294.6620 13.9009
FepEnergy: 513000 -97770.8231 -97766.6044 -396.4073
-392.0244 8.6016 23.9493 295.1816 13.0116
FepEnergy: 513010 -97850.6248 -97845.8599 -418.1019
-412.9736 9.8933 23.9379 297.4099 12.6982
FepEnergy: 513020 -97938.2812 -97933.9681 -148.3760
-142.1532 10.5359 23.9273 293.6370 12.6650
FepEnergy: 513030 -97990.5394 -97986.2606 -177.2464
-170.8289 10.6963 23.9169 294.7636 12.6403
FepEnergy: 513040 -97874.0758 -97869.7209 -318.0767
-311.3665 11.0651 23.9070 295.1473 12.6343
FepEnergy: 513050 -98150.4388 -98146.0149 -88.0099
-82.4746 9.9592 23.8966 296.2144 12.6058
FepEnergy: 513060 -97754.4007 -97749.3315 -257.1320
-251.8422 10.3590 23.8862 294.3151 12.5853
FepEnergy: 513070 -97882.2703 -97877.5356 -185.0700
-180.0540 9.7506 23.8755 294.4455 12.5416
FepEnergy: 513080 -97910.4286 -97905.4378 -198.4684
-194.5833 8.8760 23.8645 295.6490 12.4579
FepEnergy: 513090 -97941.2920 -97936.2340 -124.5519
-119.4861 10.1237 23.8537 296.2563 12.3912
FepEnergy: 513100 -97816.7706 -97811.4879 -361.0494
-355.4669 10.8653 23.8436 295.3303 12.3817
FepEnergy: 513110 -98010.7182 -98005.3038 -194.2710
-188.4203 11.2651 23.8340 297.2601 12.3795
FepEnergy: 513120 -98201.7522 -98195.8873 -126.9662
-120.7953 12.0358 23.8246 298.7064 12.3776
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