So this is more of a complex problem, and my masters thesis could greatly benefit if I find an answer to this.

Essentially, I have a supramolecular inclusion complex. There is this molecule A (the host), and another molecule B (the guest). There are literature studies pointing that the inclusion complex (A+B) is much more stable in vivo than molecule B by itself.

So, there are two ways in which A and B can interact, and lets call them interaction from the "top" and from the "bottom", and my goal is to find the more stable interaction among the two using computational chemistry. The idea is to simply compare the energies of both the complex, and then compare the energy of the molecule before complexing.

The problem with this idea is, how do you model both these "top" and "bottom" complexes? I have the equilibrium geometry of both A and B separately, but if I combine them and minimise the energy, there is no guarantee that it would orient itself in the most stable state, instead, it would just form the closest stable structure. To put it better, the molecule would fall into the closest local minima, and not the global minima.

How do you mitigate this problem? There could be hundreds, or maybe thousands of local minimal to sift through, so finding that manually could be a cumbersome nightmare.

Any inputs on this would be game changing for me. Thanks!


There are some other DFT studies on the same inclusion complex in the literature, and they have all modelled the complex only in the "top" orientation (maybe they think it is the more stable form), but they still do not claim that it is the global minima structure. Additionally, I found the crystal data for the same "top" configuration, so that could at least be a starting point, but I am still stuck on the "bottom" orientation.

Someone suggesting docking studies to me, but it is such a low level theory to depend upon for energy calculations of a complex. I do not know if I should trust molecular dynamics (or classical physics) to that degree.



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