[AMBER] Calculation of ligand restraints in TI

From: Josiah Bones <josiah.bones.anu.edu.au>
Date: Thu, 17 Jun 2021 01:13:46 +0000

Hi there!

I am just reaching out for some help as to the behaviour of AMBER20 pmemd.cuda in how it deals with the 6DoF restraints commonly employed in absolute binding free energy calculations, where the ligandís movement is restrained in a binding pocket. These calculations typically utilise two main simulations (one to decouple ligand from protein, and another for decoupling the ligand in water). From my understanding, there is then the requirement of running an additional simulation to capture the free energy of turning on the restraints of the ligand to the protein, and finally an analytical calculation to remove them.

>From reading recent works examining the changes in AMBER20 to the TI capabilities, I am suspecting, but not certain, that the restraints are already calculated in the ligand+complex simulation, removing the need for an additional simulation. Is this assumption correct, and is anything needed to be done to ensure the correct behaviour? And does this contract the requirements of such an ABFE calculation in a single smoothstep process using only two simulations: complex+ligand(restrained), water+ligand(unrestrained), and then the analytical calculation to account for the restraints?

Thank you kindly for any assistance,

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Received on Wed Jun 16 2021 - 18:30:02 PDT
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