Is it not that when I say “not exist” it denotes void space. Can we have void space in our simulations? Isnt it unrealistic?
I am sorry for bugging you with queries.
Regards
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________________________________
From: Charles Lin <Charles.lin.silicontx.com>
Sent: Thursday, October 3, 2019 12:15:51 PM
To: AMBER Mailing List <amber.ambermd.org>
Subject: Re: [AMBER] Thermodynamic integration
You don't need dummy atoms because your timask1 determines one endpoint and timask2 determines the other endpoint, so at one end point your ethanol exists, and at the other endpoint your ethanol doesn't exist.
Use this tutorial:
http://ambermd.org/tutorials/advanced/tutorial9/index.html
Absolute binding free energy is kind of like a special case of relative binding free energy, where instead of having another molecule as your second endpoint you're essentially disappearing your molecule.
-Charlie
On 10/3/19, 9:41 AM, "Debarati DasGupta" <debarati_dasgupta.hotmail.com> wrote:
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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:
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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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