Hi Ying-Chieh,
To add some more to what Jason said - accepting the fact that your
simulation parameters appear to be very different (are you definitely
using softcore in amber11 for example) this also looks to me like a case
of the results being hopelessly under converged. 600,000 steps is only
1.2ns which likely means your error bars on the sampling are huge. So a
good chunk of that difference could be coming from there. Try doing 5 or
so repeats of your AMBER 11 calculations with different random seeds /
initial structures and see what the variation is in the results you get.
As with any paper I receive where people do free energy calculations I
always ask them to do multiple repeats or ideally plot the free energy
obtained as a function of cumulative sampling length - the last one people
rarely do - I think because when they try it it is a real eye opener into
how unconverged the calculations typically are. You try this yourself to
see.
Take you 600K steps from the AMBER 11 simulation. Throw away all but the
first 10K and calculate the delta delta G and then plot that on a graph
where the X axis is sample points and the Y axis the DDG obtained. Then
repeat throwing away all but the first 20K, add that to the plot. Then
30K, then 40K etc all the way up to the full 600K - it's probably best to
script this. See what the plot looks like and it should give you a nice
visual idea of how the run is converging.
All the best
Ross
On 5/14/14, 4:37 AM, "Jason Swails" <jason.swails.gmail.com> wrote:
>On Wed, 2014-05-14 at 18:21 +0800, Ying-Chieh Sun wrote:
>> Hi,
>>
>>
>>
>> We are learning TI computation for protein-ligand binding using pmemd of
>> amber14. We used 3-step protocol ((1)switch charge off, (2) vdw
>> transformation, (3)switch charge back on) to compute Delta Delta G of
>>two
>> ligand binding with the same protein.
>>
>>
>>
>> The results of the vdw transformation are summarized below:
>>
>>
>>
>> Delta G (Complex) Delta G(Solution)
>>
>> -1.6746+-4.7307 -0.4455+-4.0797 (pmemd of amber14: ligand charge:
>>BCC
>> charge!)
>>
>> -10.8895+-6.0608 -13.1352+-5.4417 (sander of amber11: ligand charge:
>>RESP
>> charge!)
>>
>>
>>
>> Because we used BCC charge this time for pmemd, we have not used RESP
>>charge
>> yet. But, in the vdw transformation, the charges are off. Therefore, I
>>think
>> the Delta G (not Delta Delta G) should be similar. But they differ by
>>~10
>> kcal/mol in the complex and solution computations, respectively. The
>>Delta
>> Delta G¹s are indeed in the similar range.
>
>The TI code in pmemd is quite new and using it is radically different
>than using the TI code in sander. Therefore, I would suggest changing
>as _few_ things as possible when carrying out your comparisons. (i.e.,
>make sure you are using exactly the same parameters in both cases to
>carry out your simulations for comparison). Any attempt to explain the
>discrepancy will most likely be unsubstantiated speculation.
>
>>
>>
>>
>> Any advice/suggestions are appreciated.
>>
>>
>>
>> We also found a typo, I think, in the output file. As shown below, it
>>should
>> be ³A V E R A G E S O V E R 600000 S T E P S² instead of 3000 S T
>>E P
>> S.
>
>No, this is correct. pmemd does not compute the energy every step (it
>only computes the energy on the steps that it needs to print the
>energy). This is done because computing the energy introduces an
>unnecessary computational cost (and if you don't need the energy, why
>compute it?). So my guess is that you printed every 200 steps for
>600,000 total steps...
>
>HTH,
>Jason
>
>--
>Jason M. Swails
>BioMaPS,
>Rutgers University
>Postdoctoral Researcher
>
>
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Received on Wed May 14 2014 - 08:30:03 PDT
