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   practical two: conformation searching

Practical Two: Conformation Searching

(1) Construct a Ramachandran type plot

MacroModel can construct Ramachandran plots for molecules. This requires a large number of calculations, so it is best to choose a simple molecule, such as one of those in the previous exercise. Start with a minimised structure, go to the ENRGY mode, and click on Drive. You will be asked how many angles you wish to rotate. Choose '2'.

The program will ask you to define two torsion angles, by clicking on four atoms to define each angle. It will also ask for the rotational increment. The default is 30o, but you can save a lot of time by entering 60o instead. Now click on Start to initiate the calculation. The computer will now calculate the molecule's energy for all points on the grid. If you chose 60o resolution for both angles, this requires thirty-six energy minimisations.

When the calculation is complete, go to the ANLYZ mode and click on Plt2D (in versions of MacroModel before V4.5, this is the Cntr (contour) button). A new window will appear. Click on Open to open the file containing the results of the previous calculation. The file will be called filename.grd. Select this and click on Process. This will draw a colour-coded Ramachandran plot.

Clicking anywhere on the plot with the middle mouse button will show you the structure that corresponds to that point.

(2) Cram's rule

Non-chelating nucleophilic attack on these two diastereomeric aldehydes (1, 2) gives opposite selectivity, even though Cram's rule states that the selectivity should just depend on the a-centre. MacroModel is used to suggest an explanation for this, based on the MM2 force field.

Draw the two molecules in MacroModel's DRAW mode. WRITE them to the files: syn_aldehyde and anti_aldehyde. Minimise each molecule using the MM2 force field. This will give you local minima.

To discover the preferred conformation of these molecules (the global minimum and any low energy conformations), a conformational search is necessary. Check you are in the ENRGY mode, select the CSRCH sub- mode (this is for Conformational Searching), and click on MCRLO. This will set up a Monte-Carlo conformational search (Described in J. Am. Chem. Soc. 1990, 112, 1419 - 1427). You will be given various options. Choose 'Automatic setup.' This will set up a Monte-Carlo search, by deciding which torsion angles need to be varied to investigate the conformational space of the molecule. You will be presented with two more dialogue boxes. Click OK in both of them. Selecting TBond will show you which bonds are being rotated (Has the program chosen well?). Click Check to provide a summary of the search and to check there are no mistakes.

Return to the minimise (MINIM) sub-mode, and click START to set the conformational search going You will have to give the search a name, for example: anti_aldehyde_mc. The search will take some time. The search will create a number of files, including: anti_aldehyde_mc.dat,, anti_aldehyde_mc.out, anti_aldehyde_mc.log. The file which ends .log can tell you how the conformational search is progressing. The job will continue if you do something else with MacroModel, and even if you log out (New command file).

If you have stopped MacroModel running, try cat anti_aldehyde_mc.log or more anti_aldehyde_mc.log to see how things are going. If you have MacroModel running, go into the ENERGY mode, and click on MONTR, to monitor how the search is progressing. The search will find the global minimum structure more quickly if it began with a low energy structure.

Usually it is not a good idea to ask the computer to do more than one thing at a time, because it spends too much of its time swapping between jobs, and not enough time working. The computer can just about cope with two things at a time, so for this practical you can start the syn and the anti conformation searches together.

You are trying to find the Global minimum energy for each structure. When the search is finished (one thousand structures investigated), you should have found the lowest energy structures several times each. This indicates that you have probably found the global minimum. If you have only found the lowest energy structure once, the search may not be complete. This would probably be because the search began with a very strained structure. If this happens, restart the search, beginning with the lowest energy structure you have.

When the search is complete, you should have a list of conformations and their energies. You can examine the results by READing in the structures from the anti_aldehyde_mc.out file. The energy of each structure will appear in the message window as you read in the structure.

Examine the low energy structures of 1 and 2. Which face of each aldehyde is more open to attack?

The conformation searches are unlikely to be completed in the time allotted to the practical. However, they will probably progress far enough to suggest an explanation for the surprising selectivity of nucleophilic attack. Leave the searches running at the end of the practical. They will probably be complete by the next session.

Questions (a) what evidence do you have that you found the global minimum structure? (b) predict the stereochemistry of the product of nucleophilic attack on each of the aldehydes (c) explain why Cram's rule may not apply to both these diastereomers

(3) Erythromycin seco-acid

The results of a conformational search on an analogue of the seco acid of erythromycin are in the file /usr/local/examples/erythro_mc.out and /usr/local/examples/erythro_h2o_mc.out.The former was done in vacuo and the latter was done using additional equations which allow for the effect of water on the molecule. How do the results differ?

This is the global minimum structure for the conformation search without a solvent model. The structure changes dramatically, when a solvent model is applied.

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