Re: [AMBER] Thermodynamic integration from Debarati DasGupta on 2019-10-03 (Amber Archive Oct 2019)

From: Debarati DasGupta <debarati_dasgupta.hotmail.com>
Date: Thu, 3 Oct 2019 13:41:17 +0000

Dear Dr Lin,

Thanks for the helpful reply.

I have some queries in my mind: SO basically I do disaapear a molecule type calculations, so if my cosolvents is ethanol ( its a 9 atom system), I have to create 9 dummy atoms for this?

Also, how abruptly will this transformation of ethanol to nothing happen?

I did not find any parameters for dummy atoms (AMBER), how to go about creating prepi, fcrmod for dummy atoms?

Also, can you elaborate a bit on the methodology of disappear a molecule type TI calculations? DO you know of a suitable tutorial?

Thanks

Debarati

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________________________________
From: Charles Lin <Charles.lin.silicontx.com>
Sent: Wednesday, October 2, 2019 11:19:52 AM
To: AMBER Mailing List <amber.ambermd.org>
Subject: Re: [AMBER] Thermodynamic integration

Hi,

I'd follow mostly the same protocol as a relative binding free energy (where ligand a transforms to ligand b), but instead of having a ligand b, your timask, scmask of those regions becomes nothing
timask2='', scmask2='',

I would also apply the virtual bond algorithm described here to keep your ligand in the pocket (described as a virtual bond here)
https://pubs.acs.org/doi/pdf/10.1021/jp505777n

These calculations are fairly expensive to calculate. Relative binding free energies converge a lot more quickly because the amount of phase space to sample is already somewhat more limited due to the presence of a ligand you already know its binding pose/pocket position. The less data you know about your system, the less likely you'll place your ligand correctly, and simple changes such as having a side chain incorrect, could vastly give different absolute binding free energy values.

-Charlie

On 10/1/19, 4:26 PM, "Debarati DasGupta" <debarati_dasgupta.hotmail.com> wrote:

    CAUTION: EXTERNAL EMAIL

    Dear All,

    I have been trying to read more about free energy calculations using TI method implemented in AMBER18. I recently did a webinar by CCG group wherein in MOE2019 they have incorporated the TI implementation setup collaborating with AMBER.

    I did read this publication too from Professor Carlos Simmerling’s webpage “ https://chemrxiv.org/articles/Blinded_Prediction_of_Protein-Ligand_Binding_Affinity_Using_Amber_Thermodynamic_Integration_for_the_2018_D3R_Grand_Challenge_4/8312375/1”
    This did throw a lot of light on how to exactly setup TI calculations in AMBER.

    I still have a very fundamental question, it may be very stupid, but I am not sure how to setup TI to calculate the absolute binding affinity of a ligand towards a protein.
    Is there something I am missing totally?
    My protein of interest is ABL-kinase and I have a done some co-solvent simulations to get some hotspots( areas of possible ligandibility); I need to calculate the binding affinity of these small cosolvents towards ABL.
    TI methods give us a “deldelG”, which is relative binding affinity, if we have a receptor (say CathepsinS) and have a set of 10+ ligands with a common core (scaffold).
    If I have one protein +1 ligand and I need to calculate the binding affinity what is the procedure to be adopted?
    Is there a tutorial to do that?

    I am not looking to do MMGBSA/PBSA on this system.

    Thanks

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Received on Thu Oct 03 2019 - 07:00:02 PDT