The Conformational module consists of a series of algorithms designed to study the conformational space of medium-sized organic molecules.

Questions about Conformations and Energy Profiles

How do I know I have the global minimum?
The only way to be sure you have the global minimum is to do a systematic search with a very large/dense grid. For example, increase the rotation count for sp3-sp3 carbon bond rotors from the default of 3 to 10. This is known to be very inefficient, and chances are that if you have a non-trivial molecule you may not have the patience required for this calculation to complete.

Our experience with medium (drug-size) organic molecules is that the Monte-Carlo algorithm, in general, does a good job of finding the global minimum. See "How do I know my MC result is good?", and "Is the global minimum the best minima?"

Is the systematic algorithm reproducible?

Yes, if you start from the same conformation. In simple molecules the systematic algorithm is almost always inclusive of all (important) minima. As molecules become more complicated the default grid size, while likely correct in finding all classes of minima, may skip some minima. For example, the single "gauche plus-gauche minus" [-120,+120] conformation of olefins might bifurcate into multiple minima as steric bulk increases. It is likely that one of the two new minima would be found using the standard systematic approach. But 'which one' would depend on the initial conformation.

Take for example this not-so-simple 1-dimensional rotation from a real molecule which is nominally a 2-fold rotor (with minima near 110, and 300).

And recall that our algorithm is

  1. Start from the original structure
  2. rigidly move (or constrain in difficult cases) the relevant dihedrals
  3. minimize to find "nearest" minima from this starting case

If we start from the 300-degree minima and assume a 2 fold rotation our algorithm will take one 180 degree step to 120 and then minimize to easily fine the minima at 110. Obviously missing the minima near 190.

Choosing a 3-fold rotor from the same 300 degree starting point we step to 180, very near the 190 minima, and to 60 which will the go downhill to the 110 minima.

However, starting from the 110 degree minima is a different story. The 2-fold rotor will find only 1 other minima as expected. Choosing the 120 degree steps of the 3-fold rotor leads to a problem as the first step lands at a peak of 230 degrees. And it seems like a 50/50 prospect of going to the 110 or 300 minima. Thus making it likely that starting from this starting point would not find the higher energy minima at 190.

Of course this story gets more complicated as the above energy curve will change measurably for as other "nearby" dihedrals change. (spinnage banging into other spinnage, or hydrogen bonding stabilizing otherwise high energy conformerations etc.)

Thus my advice if you "want to find ALL minima" or make the results "identical regardless of the starting point"

  1. You probably do not want to find ALL minima. We believe our defaults find a reasonable sampling of the low energy minima.
  2. Yet, if you really do want a fuller coverage of conformation space you need to increase the fold count; ie for 3 fold rotations use 4 or 5 knowing that this is overkill in many cases and will greatly lengthen the job time.

Are Energy Profiles reproducible
Similar to the previous question; yes they are reproducible assuming you start from the same conformation. An example of the initial conformer affecting systematic results can be found by inspecting an 8 member carbon chain: "C1-C2-C3-C4-C5-C6-C7-C8". For illustrative purposes consider the central "C4-C5" bond as we rotate it 360 degrees; from -180 to 180 degrees. If one starts in the all "trans" conformation, we find that as we rotate the "C4-C5" bond the final conformation of 360 degrees is identical to the initial at 0 degrees. However, if the initial conformation had a number of kinks in it, we might discover that at the 120 degree mark, the C1 and C8 ran into each other. To relieve this steric problem the other dihedral angles, will relax, likely changing by more than 100 degrees and falling into new energy wells. As we continue the coordinate driving of the central C4-C5 angle to trans (180), we might find that the final conformation is not the same as the initial conformation because these other dihedrals have changed.

A contrived example of profile hysteresis

This kind of hysterisis is to be expected; the algorithm changes 1 degree of freedom and then finds the "nearest" minimum with this constraint. In complicated systems with multiple minima hysteresis like effects can and do happen. A silly cartoon of how this can occur given an ugly two dimensional energy map is shown below. Going from one "blue minima" to the other is not reversible

The point of this graph on the left is that both the green path and the yellow path make some big jumps when the minima they are in is no longer stable. If they were "quantum objects" they might tunnel through that big red mountain separating them, or if they were "good hikers" they might find the pass between the two red peaks. (These paths paths are shown in the plot on the right.)

Is the global minimum the truth?

The global minimum is often the most interesting, and at the very least, is often representative of an equilibrium conformer found at room temperature. However, what conformation is 'best' depends on what you are looking for. There are often many other variables that conformational analysis ignores, including the effect of solvent and the quality of the energy reported at the given theory level.

How should I use QM methods with Conformation Analysis?

Because QM methods take more time than molecular mechanics (by orders of magnitude), it is usually a mistake to try conformational algorithms with QM methods. Typically, one uses the MMFF mechanics force field to generate a list of low energy conformers. This list is then resubmitted at the desired QM level as either an "equilibrium geometry" or "single point energy" calculation. The original MMFF conformers may change geometry slightly and their relative energies will likely differ.

For small systems (1 or 2 degrees of freedom) it is sometimes possible to use conformational analysis to scan conformer space with a QM method. However, the time required, (as well as the possibility of bad initial conformers with steric problems causing the breaking and forming of bonds), require that users apply caution when applying QM methods to conformational analysis.

A further warning about "bad" initial conformers: It is highly likely that in doing a full conformer search one may start in an unfavorable position. For example, a gauche+/gauche+ conformer in propylene. At the beginning of the minimization two hydrogens may be within 0.25 Angstroms of each other. With molecular mechanics this "bad" starting position is easily handled, but with quantum chemical methods "chemistry" will occur; resulting in the breaking and reforming of bonds. You will likely not end up with the molecule you started with. Given that this is probably not what is intended, and that it will take a very long time to rearrange all atoms into a "new" molecule, you will be lucky if the job runs out of 'geometry cycles' before taking up too much computer time. The best approach is to "know" that you are starting at a good conformer. This is another reason why it is a good idea to start with MMFF conformers.

This said, beginning in Spartan"18, Wavefunction has introduced multi-step recipes taking advantage of the strengths of both MM and QM models to provide accurate Boltzmann distributions. Further, when utilized in conjunction with the NMR Spectrum task, these also provide a Boltzmann averaged NMR spectrum,. See the Dealing With Conformationally Flexible Molecules topic: Menu -> Activities -> Topics, from within Spartan.

How do I tell if the Monte Carlo results are correct?
The only way to know for sure is to compare results with a complete, systematic calculation. (see How do I know I have the global minimum?.) You can build your confidence in the Monte Carlo results by restarting the search from different initial conformations. If multiple starting points yield the same "global minimum" you should have confidence that the algorithm is spanning the conformational space fairly well.

What are the details of the algorithm?

How can I modify the algorithm?
Within the 'Set Torsions' mode, you can choose the bonds and ring atoms involved in the conformational search. This is done by double-clicking on either the desired bond or atom. When a bond or atom is selected for rotation, a type-in box will appear. This box is used to enter the number of increments in the rotation. For example, if the value of 3 is entered, rotations of 0, 120 and 240 degrees will be applied. If you do not specify bonds or ring atoms, Spartan will use heuristics to decide which elements are relevant in attaining new conformers. Unless you have some chemical insight as to the relevant rotatable members, Spartan's default selections will typically provide good results. Additionally, several keywords will modify calculation details.

What do the fold numbers mean in the Set-Torsions mode?

On bonds, the fold number is simply the number of gross conformers. So for '3' there are assume 3 states, each 360/3=120 degrees apart. Thus each move is +- 120 degrees. A fold number of 2 would mean two conformers, each +- 360/2=180 degrees.

On atoms the fold number contains more specific information. An atom fold number of 3 means an "Osawa wag" is preformed. (A 4 implies a coupled Osawa wag in a cyclohexane like ring.) In the case where the number contains 3 digits, the ones-digit is either 3 or 0 for Osawa wag or no wag, respectively. The hundred's digit, if present indicates that an inversion will be tried. This may occur on asymmetric, non-planar, trivalent nitrogens.

Use the keyword PRINTLEV=2 when the job is run to see more information on what precisely is being flipped and/or rotated.

Interpreting the output file:

Description of the columns:

Why does the output say it is removing molecules from the list and how is it deciding what to remove?

Any conformer that has an energy greater than WINDOW (10.0 kcal/mol) of the lowest energy conformer is thrown away. If there are more than MAXCONFS (100) conformers with acceptable energies the program will discard conformers with the goal of keeping as diverse a group as possible, while, at the same time as keeping the lowest energy conformers.

How many cycles will my molecule take? or
Will my molecule use the Systematic or Monte Carlo method?

The number of cycles a molecule will take depends on the type and number of rotatable bonds. Each rotatable bond has a fold number. (This fold number can be modified in the 'Set Torsions' mode.) For example sp3-sp3 bonds have a default fold number of 3 because these bonds usually have 3 minima 120 degrees apart. For systematic methods the number cycles is the product of all the fold numbers. For Monte Carlo methods the default number of cycles is the square of the sum of all folds. (This equation is a purely empirical formula; experience has shown it to be adequate.) One can limit this value to an upper limit using the "Maximum Conformers Examined" field in the setup panel, and increase the value above the default using the McConfs= keyword.

The program will choose between the Systematic or Monte Carlo method by choosing the one with the fewest default conformer tries (unless the SEARCHMETHOD keyword is used to override the default).