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

From: David A Case via AMBER <>
Date: Thu, 29 Sep 2022 09:47:56 -0400

On Thu, Sep 29, 2022, Liao via AMBER wrote:

>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.

Look at it this way: only the initial and final states represent physically
realistic systems. In the final state, the atoms in the "initial" ligand
are decoupled from the environment, so it won't matter if they are
surrounded by a big vacuum, or have apparent clashes with waters. (Similar
argument for the initial state.)

At intermediate lambda values, one has a mixed system that can only be
represented on in a computer simulation, not in the lab. These systems may
indeed have strange-seeming properties, but are only used to provide a free
energy connection between the initial and final states.

....hope this helps....dac

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Received on Thu Sep 29 2022 - 07:00:03 PDT
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