You simulation used only 5 blocks of 5 multiscale moves per λ value. This was not sufficient to converge the free energy average. To converge the average, you need at least 100 blocks of 50 multiscale moves. Such simulations take about 6-12 hours to complete (depending on the size of the solute and choice of QM method). Since you don’t have time today to do this, example output for each semi-empirical method has been provided here. Choose the file corresponding to the semi-empirical method that you have chosen and and unpack it into your directory, e.g. if you chose “DFTB”, then download the file “DFTB.tar.bz2” and unpack it using the command;

The result will be a directory containing the output from 100 block quantomm simulations on both PHE and TRP. If you are interested, you can visualise the sampling performed in each simulation at λ = 0 using VMD using the command;

tar -jxvf DFTB.tar.bz2

EXERCISE 5: ANALYSING CONVERGED QUANTOMM SIMULATIONS

Use “sire.app/bin/analyse_freenrg” to calculate the PMFs for PHE and TRP for your chosen semi-empirical method. Plot these PMFs together in a graph. Calculate the difference in free energy between the QM/MM and MM models for PHE and TRP.

QUESTION 5.1 - How do the PMFs you have calculated over 100 blocks compare to the PMFs you calculated using the short simulations in the last step? Why is there a difference?

QUESTION 5.2 - The PMF shows the free energy needed to move from the QM/MM to the MM model of the side-chain. Do the PMFs show that your chosen QM/MM model interacts more strongly or more weakly with water than the MM model?

If you get stuck or need help, you can take a peek at this model answer for exercise 5.

vmd METHOD/SIDECHAIN/output/coords*0.00*.pdb

where “METHOD” is the semi-empirical method and “SIDECHAIN” is the side-chain you want to view. For example, to view the λ = 0 (QM/MM) sampling for TRP using DFTB, type;

vmd DFTB/TRP/output/coords*0.00*.pdb

Similarly, to view the λ = 1 (MM) sampling for TRP using DFTB you would type;

vmd DFTB/TRP/output/coords*1.00*.pdb

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