Dear Prof. Case,
Yes, I believe I have done something wrong. As I found the number is too large. I did the umbrella sampling for a drug dissociation process. Coor X is defined as the reaction coordinate between the drug the protein. In amber 10, a k value of 1 was used.
Using WHAM's latest version, I get the results as follows:
#Coor Free +/- Prob +/-
1.500000 inf nan 0.000000 nan
2.500000 inf nan 0.000000 nan
3.500000 inf nan 0.000000 nan
4.500000 33.295096 nan 0.000000 nan
5.500000 21.643006 nan 0.000000 nan
6.500000 12.256919 nan 0.000000 nan
7.500000 3.359538 nan 0.010457 nan
8.500000 0.000000 nan 0.981880 nan
9.500000 3.589868 nan 0.007659 nan
10.500000 9.165281 nan 0.000004 nan
11.500000 17.138988 nan 0.000000 nan
12.500000 26.654084 nan 0.000000 nan
13.500000 33.393167 nan 0.000000 nan
14.500000 42.004000 nan 0.000000 nan
15.500000 45.363139 nan 0.000000 nan
16.500000 50.638543 nan 0.000000 nan
17.500000 57.254489 nan 0.000000 nan
18.500000 65.907824 nan 0.000000 nan
19.500000 76.438530 nan 0.000000 nan
20.500000 82.116880 nan 0.000000 nan
21.500000 87.786696 nan 0.000000 nan
22.500000 92.968858 nan 0.000000 nan
23.500000 96.640545 nan 0.000000 nan
24.500000 101.400175 nan 0.000000 nan
25.500000 100.752261 nan 0.000000 nan
26.500000 100.933167 nan 0.000000 nan
27.500000 101.615512 nan 0.000000 nan
28.500000 102.182606 nan 0.000000 nan
29.500000 103.627676 nan 0.000000 nan
30.500000 106.691590 nan 0.000000 nan
31.500000 110.057231 nan 0.000000 nan
32.500000 110.304851 nan 0.000000 nan
33.500000 111.464727 nan 0.000000 nan
34.500000 113.234154 nan 0.000000 nan
35.500000 114.639814 nan 0.000000 nan
36.500000 114.782833 nan 0.000000 nan
37.500000 113.876368 nan 0.000000 nan
38.500000 113.511553 nan 0.000000 nan
39.500000 113.790089 nan 0.000000 nan
#Window Free
#0 0.000000 nan
#1 -9.348947 nan
#2 -18.203040 nan
#3 -26.024704 nan
#4 -32.030254 nan
#5 -36.268508 nan
#6 -39.477532 nan
#7 -41.376515 nan
#8 -41.374568 nan
#9 -39.449902 nan
#10 -36.117836 nan
#11 -31.886494 nan
#12 -26.536331 nan
#13 -20.278271 nan
#14 -12.733186 nan
#15 -4.389079 nan
#16 3.788553 nan
#17 9.816979 nan
#18 15.018555 nan
#19 20.989948 nan
#20 27.762606 nan
#21 35.624387 nan
#22 44.374197 nan
#23 51.925036 nan
#24 56.779238 nan
#25 58.904169 nan
#26 59.267176 nan
#27 59.882095 nan
#28 60.627343 nan
#29 61.963099 nan
#30 64.081690 nan
#31 66.996785 nan
#32 68.718059 nan
#33 69.839396 nan
#34 71.388874 nan
#35 72.598798 nan
#36 72.244506 nan
#37 71.764558 nan
#38 71.739078 nan
#39 72.352771 nan
It seems to me if I measure the energy difference from the starting point (i.e. X=0, the energy different is 72 kcal/mol). However, if I measure the energy barrier from the energy minimum (i.e. X=7), the energy barrier could be as large as 110 kcal/mol.
However, not matter how, according to the comments from you, the energy value of 72 or 110 still too high, is it?
I am wondering if I have misunderstand the unit of the WHAM output file, it is given in Kcal/mol or KJ/mol?
I understand the WHAM taking 1/2 of k value into account, so, in WHAM
calculation, I have used k value = 2 instead as suggested
in the manual. When I am using k=1 in amber, should I use k=2 in WHAM calculation?
I have done the simulation per window for 250 ps. The first 100 ps is equilibrium, the last 150 ps is for production. The PMF profiles of last 150 ps and the middle 100 ps are similar. So, I believe the PMF profile has been converged.
Could you please kindly give me some more hints for potential wrong things that I may have done?
I believe the binding energy between the drug and the protein is ~ 50 kcal/mol as indicated by MM-PBSA calculation for the drug-protein binary complex MD simulation. Experimentally, I have only done the half-live of drug-protein complexes, which remains stable in 1 min under a high salt (0.3 M) experimental condition.
By the way, is the MM-PBSA or MM-GBSA energies results given in the unit of kcal/mol too?
Best regards and many thanks,
Catherine
> Date: Sun, 19 Dec 2010 13:44:38 -0500
> From: case.biomaps.rutgers.edu
> To: amber.ambermd.org
> Subject: Re: [AMBER] Any one reported a drug dissociation barrier could be as high as 100 kcal/mol ?
>
> On Mon, Dec 20, 2010, Catein Catherine wrote:
> >
> > Did any one read any publication reported that the potential of mean
> > force for a drug dissociation from its receptor could be as high as 100
> > kcal/mol? Is it a reasonable number if a large conformation change in
> > protein is needed to remove the drug from the receptor?
>
> This is not a reasonable number. The free energy required to completely
> unfold the protein (at which point the drug would dissociate) is probably less
> than 10-20 kcal/mol. So, the high number you allude to sounds like a
> computational artifact.
>
> (This assumes that there is not a covalent connection between the drug and the
> protein.)
>
> ....dac
>
>
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Received on Sun Dec 19 2010 - 21:30:04 PST
