Practicum 5 - QM/MM

QM/MM calculations. 

Since about 1980, the involvement of QM/MM calculations in decoding biochemical processes has been incessantly increasing. On the practical aspect, performing accurate QM/MM calculations on protein systems requires strong dedication and benchmarking. Amongstthe most time requiring steps are:

  1. The test of the method (QM, MM, basis set, force field...)
  2. The test of the partition (where to position the link atoms, what are the best cuts for representing the real system, what are the best cuts to product faster convergences, ...)
  3. The parametrization of non biological regions of the systems and the interface between QM and MM spaces

The preparation of QM/MM calculations and their analysis are rarely optimized for an end user.


Setting up and testing a QM/MM approach on a protein is a complex exercise in general terms but more particularly for a short practicum like those that you are introduced in this class.

When we worked on the NCS holo-structure, we could appreciate that the its chromophore on its own is substantially large (81 heavy atoms). One could easily imagine that using QM/MM approaches on this sole molecule would disminuish substantially its computational cost. That will be our task from now on: testing QM/MM on the NCS chromophore.

Preparing the Chromophore for QM/MM calculations.

As usual, download the 1nco structure of the NCS complex in UCSF Chimera, clean it from solvent and delete non interesting stuff. Only keep only the chromophore in your session. Add the hydrogen and then save the pdb file.

Then open the program GAUSSVIEW which is your interface with the GAUSSIAN program.

1. Our first calculation will consist in a minimization under the QM/MM framework that allows Gaussian. This method is called ONIOM and is based on a substrative scheme. 

Discuss the way substractive QM/MM methods work.

2. We will calculate the structure using a pm6:uff approximation.

first consider the partition that you think would be interesting. Bare in mind the possibility to calculate a reactive profile consistent with the reaction discussed here. Prepare the input with the help of the  tutor and acoording to the partitioning you had in mind. Our first set of calculations will be carried out using a mechanical embedding approximation.

Discuss:

1. Does the calculation rapidely converge?

2. How the structure of the chromophore changed from the initial form. Could you see any possible reason of those changes?

3. if different partitions have been generated in the classroom, do comparative analysis with the results of your classmates.

Are QM/MM calculations really worthy?

We will increase the amount of computational ressources required. Repeat the precedent calculation with electronic embedding on the one side and a full pm6 calculation on the other.
Compare the different series of calculations (shape of the minimum structure, time to reach the convergence, etc...)

A tast of reactivity.

Try to increase the work towards the thioadducts described in the Myers' paper.  Minimize reactants and products and try to establish how you could discriminate from QM/MM calculations between the different mechanisms.
Once done, perform the calculations necessary to carry out the entire study.

 

Careful: In case the  calculations lasts too much, you may prepare to send calculation in background. Do the following:

1. save the input file from gaussview in a given location in your computer (i.e. /root/Sugar_free.com)

2. run /opt/g09/g09 < Sugar_free.com> Sugar_free.log &

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