[AMBER] Which molecule should the environment feel, in TI simulations?

From: Liao via AMBER <amber.ambermd.org>
Date: Thu, 29 Sep 2022 06:39:14 +0800

Dear List,
I've been trying to get a thorough and detailed understanding of the process of TI (or FEP in general). And I did some tests, modifying the official AMBER pmemd Thermodynamic Intergration tutorial (https://ambermd.org/tutorials/advanced/tutorial9/index.html) where Benzene is alchemically mutated into phenol.
After realizing there is only 1 trajectory generated for each lambda window, and this one trajectory contained both ligands (i.e. the initial and final state of the mutation for that window), one of my concerns is which ligand does, or should, the environment feel? The environment I mean the waters, or protein.
In order to try to answer my own question, I modified the phenol in the tutorial into a t-butyl-ether. So it is bulky enough for me to see from the trajectory. From the ligand-only trajectories, what I saw was, for the vdw mutation stages, initially the t-butyl will clash with water (since it doesn't really exist yet). Later on, as the lambda windows progress, water clearly gets displaced.
But then this generates a dilmemma to me-if the environment in simulation senses the final-state ligand, then that means the potential energy measurements for the initial state will have a big vacuum around it. That's not natural at all. But if the environment in simulation senses the initial-state ligand, that may seem even worse because water will be totally clashing with the final-state ligand's t-butyl.
How is this problem address if at all? I may be missing something here.
Thanks for all your valuable insights!
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Received on Wed Sep 28 2022 - 16:00:03 PDT
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