Hello,
I performed a series of free energy calculations on three complexes
based on three different X-rays of the same enzyme with the same ligand
in there (MDs over 10 ns - complex1, 12 ns - complex2 and 15 ns
-complex3 where performed respectively).
All calculations run fine, but I have some problems in judging the
results of one of them, due to an increased INT value for the ligand
occurring in one of the simulations, which results in a very high PBTOT,
GBTOT and GAS values (-780, -760 and -800, approx). This delta G values
doesn't sound physically reasonable to me, since the ligand is the
substrate, converted very fast to the product by oxidation.
I checked the respective top and crd files to secure that the
coordinates are ok, and all of them seems working fine. As already
pointed out, the only "strange" value is the INT for the ligand in
complex 3.
The binding site of the ligand (obtained by X-ray) has a hydrophobic
character and is most exposed to the solvent in the last complex (the
channel to the solvent is progressively increasing in radius while the
15 ns MD).
These are the three output files of the statistics, the last one the
"problematic" one:
complex 1:
> # COMPLEX RECEPTOR
> LIGAND
> # ----------------------- -----------------------
> -----------------------
> # MEAN STD MEAN STD
> MEAN STD
> # ======================= =======================
> =======================
> ELE -7164.99 94.86 -7145.51 92.44
> -20.12 0.45
> VDW -1207.18 24.44 -1178.26 24.28
> 11.13 2.04
> INT 5852.17 51.48 5796.13 52.42
> 56.23 3.55
> GAS -2520.00 80.33 -2527.64 77.74
> 47.24 4.17
> PBSUR 102.84 1.63 104.61 1.68
> 3.47 0.02
> PBCAL -3581.93 77.68 -3591.93 74.90
> -17.05 0.46
> PBSOL -3479.09 77.49 -3487.32 74.69
> -13.58 0.45
> PBELE -10746.92 36.30 -10737.44 35.88
> -37.17 0.38
> PBTOT -5999.09 44.42 -6014.96 44.99
> 33.66 4.16
> GBSUR 102.84 1.63 104.61 1.68
> 3.47 0.02
> GB -3612.96 82.01 -3608.14 79.56
> -16.91 0.48
> GBSOL -3510.12 81.90 -3503.53 79.40
> -13.44 0.47
> GBELE -10777.95 28.03 -10753.65 28.07
> -37.03 0.30
> GBTOT -6030.12 42.86 -6031.17 44.43
> 33.80 4.17
> TSTRA 17.06 0.00 17.06 0.00
> 12.80 0.00
> TSROT 17.62 0.01 17.62 0.01
> 10.13 0.00
> TSVIB 3154.65 17.00 3133.25 17.81
> 14.83 0.01
> TSTOT 3189.34 17.01 3167.93 17.81
> 37.76 0.01
>
> # DELTA
> # -----------------------
> # MEAN STD
> # =======================
> ELE 0.64 3.88
> VDW -40.05 2.01
> INT -0.19 0.12
> GAS -39.59 4.50
> PBSUR -5.25 0.18
> PBCAL 27.05 5.88
> PBSOL 21.81 5.93
> PBELE 27.69 4.02
> PBTOT -17.79 3.96
> GBSUR -5.25 0.18
> GB 12.09 3.89
> GBSOL 6.84 3.95
> GBELE 12.73 1.03
> GBTOT -32.75 1.95
> TSTRA -12.79 0.00
> TSROT -10.12 0.01
> TSVIB 6.56 23.35
> TSTOT -16.35 23.35
Complex 2:
> # COMPLEX RECEPTOR
> LIGAND
> # ----------------------- -----------------------
> -----------------------
> # MEAN STD MEAN STD
> MEAN STD
> # ======================= =======================
> =======================
> ELE -7475.09 86.13 -7442.27 85.87
> -20.29 0.56
> VDW -1190.61 26.70 -1164.66 26.38
> 11.09 1.64
> INT 5814.36 54.50 5757.17 54.48
> 57.18 4.58
> GAS -2851.35 89.66 -2849.76 89.37
> 47.98 4.55
> PBSUR 104.81 2.23 106.45 2.27
> 3.47 0.02
> PBCAL -3361.36 77.07 -3375.23 77.76
> -17.05 0.49
> PBSOL -3256.55 75.80 -3268.78 76.47
> -13.58 0.48
> PBELE -10836.46 30.83 -10817.49 30.17
> -37.34 0.40
> PBTOT -6107.90 53.44 -6118.53 53.54
> 34.41 4.55
> GBSUR 104.81 2.23 106.45 2.27
> 3.47 0.02
> GB -3355.29 75.26 -3362.61 75.27
> -16.81 0.58
> GBSOL -3250.48 74.13 -3256.16 74.10
> -13.34 0.57
> GBELE -10830.38 26.92 -10804.88 26.78
> -37.10 0.34
> GBTOT -6101.83 52.79 -6105.92 52.84
> 34.64 4.51
>
> # DELTA
> # -----------------------
> # MEAN STD
> # =======================
> ELE -12.54 6.33
> VDW -37.04 2.70
> INT 0.00 0.00
> GAS -49.58 6.02
> PBSUR -5.11 0.22
> PBCAL 30.91 5.69
> PBSOL 25.80 5.70
> PBELE 18.37 4.61
> PBTOT -23.78 4.03
> GBSUR -5.11 0.22
> GB 24.13 5.24
> GBSOL 19.02 5.28
> GBELE 11.60 1.87
> GBTOT -30.56 2.27
Complex 3 (the tricky one!):
> # COMPLEX RECEPTOR
> LIGAND
> # ----------------------- -----------------------
> -----------------------
> # MEAN STD MEAN STD
> MEAN STD
> # ======================= =======================
> =======================
> ELE -7364.10 88.38 -7328.19 88.06
> -9.80 0.43
> VDW -1169.56 28.88 -1142.30 28.51
> 31.96 3.46
> *INT 5807.69 63.58 5751.70 63.69
> 773.72 32.78*
> GAS -2725.96 85.65 -2718.79 87.38
> 795.88 33.10
> PBSUR 103.83 1.48 105.38 1.48
> 3.47 0.01
> PBCAL -3319.88 68.07 -3337.57 68.75
> -17.01 0.46
> PBSOL -3216.05 68.01 -3232.19 68.69
> -13.55 0.46
> PBELE -10683.98 37.74 -10665.77 36.09
> -26.81 0.46
> *PBTOT -5942.02 55.96 -5950.98 56.51
> 782.33 33.12*
> GBSUR 103.83 1.48 105.38 1.48
> 3.47 0.01
> GB -3369.82 75.95 -3379.41 76.20
> -16.85 0.47
> GBSOL -3265.99 76.04 -3274.02 76.28
> -13.39 0.47
> GBELE -10733.92 29.53 -10707.60 28.88
> -26.65 0.29
> *GBTOT -5991.96 63.46 -5992.82 63.51
> 782.49 33.19*
> TSTRA 17.07 0.00 17.06 0.00
> 12.80 0.00
> TSROT 17.64 0.01 17.64 0.01
> 10.13 0.00
> TSVIB 3156.01 17.56 3134.40 17.31
> 17.09 1.39
> TSTOT 3190.72 17.57 3169.10 17.31
> 40.01 1.39
>
> # DELTA
> # -----------------------
> # MEAN STD
> # =======================
> ELE -26.11 6.22
> VDW -59.22 3.68
> INT * -717.72 32.33*
> GAS *-803.05 33.62*
> PBSUR -5.02 0.09
> PBCAL 34.70 3.72
> PBSOL 29.68 3.77
> PBELE 8.60 4.44
> PBTOT * -773.36 33.20*
> GBSUR -5.02 0.09
> GB 26.44 4.28
> GBSOL 21.42 4.33
> GBELE 0.33 2.57
> GBTOT * -781.63 32.99*
> TSTRA -12.79 0.00
> TSROT -10.12 0.01
> TSVIB 4.52 18.65
> TSTOT -18.39 18.66
Can anyone help me in judging these results? Where can there be a
mistake in my complex 3 or are the values ok?
The ligand does not show any strange distorted conformation and all
bonds are fair enough.
I attach crds of complex and ligand used for the mmPBSA calculation of
complex 3 and the ligand and complex topology files for seek of clarity.
Thanks in advance,
Matthias Negri
Pharm. & Med. Chemistry
University of Saarland
D-66041
Received on Wed Aug 19 2009 - 19:39:04 PDT
