How do I find the geometry of a tetramer assembly?

Question

What's the best way of finding optimal geometry and minimal energy for tetramer with H-bonds? I know where H-bonds should be, but do not know their length.

Should I just draw randomly 4 molecules, freeze H-bonds and then do some calculations (e.g., semi-empirical) to get minimal energy or is it done another way?

All four molecules, as we guess, should assemble in the way so they make kinda 'tunnel'. And is running conformer calculations valid? Or in that case it calculates conformers of individual molecules in tetramer, not the whole structure?

Answer 1

In general, this is a very tricky problem. At its root, it's quite similar to solving the question of predicting a crystal structure -- you want to know the interaction between multiple molecules via hydrogen bonds and other electrostatic non-covalent interactions.

Here's the best general procedure:

1. Perform a conformer search on an individual molecule. As you guess, a "conformer search" (in this case in Spartan) is not going to sample different configurations of the supramolecular system. Worse, there's no guarantee that the lowest energy conformer is the one that's found in the tetramer. Still, it's better to start with a low energy conformer, since that's the most likely one.
2. Attempt to find a low-energy dimer configuration by copy/pasting your molecule. Consider how the hydrogen bonds might match. If you have some knowledge of the interactions great. I might consider, for example that the N-C=O combination you've circled in the bottom left corner probably matches up with the two amines above them (e.g., the dimer has one copy flipped "upside down" compared with this depiction).
3. Optimize the dimer geometry using hydrogen bond constraints and a reasonable computational method. Here, I would not use RM1 or PM3, since both methods do not include hydrogen bonding terms. I would use some flavor of PM6 or PM7 if you want to use semiempirical methods, or I'd try some type of dispersion-corrected DFT method, e.g., B3LYP-D3 or $\omega$-B97X-D.
4. Copy/paste the dimer to try to build up a tetramer structure.

I know some research groups have tools that somewhat automate this process, but I don't know of any that are currently widely-available and user-friendly. This is very much still an active area of research.

Moreover, as a human, you can often spot "how things fit" better than most automated strategies.

Good luck!