Re: Some Basic queries for FEP and TI

From: Debadrita Basu (
Date: Mon Mar 22 2021 - 06:48:57 CDT

Thank you for your reply. I could understand the problems associated with
such calculations. Moreover, I would like to ask if the ligand is neutral
will that lessen the complications or if we do the FEP to know the
effect of a structural water(which is also neutral) will that have lesser

On Mon, Mar 22, 2021 at 1:11 AM Brian Radak <> wrote:

> 1) Using the whole protein is almost always technically more correct, but
> makes sampling more expensive and harder to converge (potentially
> unattainable on such large a system). Unless you think there are important
> conformational changes involved, I would consider a specialized strategy
> for your quantity of interest.
> 2) Charge changing perturbations do cause a shift in dG values due to a
> change in the zero of energy arising from PME. However, the shift vanishes
> when the periodic box is large and the mean dielectric is high (eg if the
> system is mostly water). I would look up the work of Rocklin, et al. on
> using continuum corrections, but other strategies may also work.
> Also, divalent ion parameters in fixed charge force fields are notoriously
> poor. You generally either get good structure or good energetics - rarely
> both. I would validate your model in someway first, bc the results are
> unlikely to just work out nicely on your first try.
> Hope that helps,
> On Sun, Mar 21, 2021, 12:21 PM Debadrita Basu <>
> wrote:
>> Hello Everyone,
>> My protein of interest has ~850 residues (quite big) where a Magnesium
>> ion is intrinsically bound. Also some ligands are known to bind to some
>> specific grooves of this protein. I wanted to see the role of Magnesium on
>> the ligand binding (ie whether it has a facilitating or inhibiting role).
>> So, I decided to carry out the FEP calculation where I discharge the
>> Magnesium atom to a dummy Magnesium atom, (in two different systems: ligand
>> bound and apo) followed by thermodynamic integration. I used CGENFF to
>> parameterize.
>> I decided to follow the FEP algorithm implemented in NAMD, but I have a
>> couple of questions in my mind:
>> 1. Whether I will get a true result by using the whole protein.
>> 2. While discharging the Magnesium atom I will end up changing the total
>> charge of the system, is that acceptable? If not, how can it be solved?
>> Hope, I get something to learn from your answers.
>> Thank You.
>> --
>> Debadrita Basu.
>> Senior Research Fellow
>> Bose Institute
>> Kolkata, India.

Debadrita Basu.
Senior Research Fellow
Bose Institute
Kolkata, India.

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