Help in reverse Free Energy perturbation - hysteresis

From: Bruno Luís Pinto de Oliveira (boliveira_at_itn.pt)
Date: Mon Oct 03 2011 - 05:24:58 CDT

Dear all,

I am new to FEP and since the last months I have gotten great help from the mailing list. Thanks to all who help me...

I am posting this message because I have a new doubt about the reverse calculation to
monitor the hysteresis.

Briefly, I would like to estimate the difference in the binding energy between a Rhenium complex and the corresponding ligand (compounds are exactly the same with the exception that the ligand lacks the metallic part Re(CO)3; the Re(CO)3 vanish).

I did the foward transformation (transformation in water and protein; lambda goes from 0 to 1) and the calculated results are in good agreement with the experimental results (I used a thermodynamic cycle that someone in a previous post confirmed that is correct; I am using 16 ps of equilibration and 80 ps of colection per lambda, 32 states, ~3ns).

Then, I used the end of the foward transformation as the starting point for the reverse simulation (lambda goes from 1 to 0).

For example, the transformation of the Rhenium complex into the ligand gave -31.33 kcal/mol (forward) and 35.34 kcal/mol (backward).
>From the literature that I read I realized that the backward transformation should display more or less the same free energy change of the forward transformation but with an opposite sign. Did I understood well?

if so can I assume that the hysteresis is acceptable???

or I need to plot the DG against the lambda as examplified in the tutorial of Christophe Chipot et al.

I did it and as you can see in the graphic the foward and backward curves do not converge.

http://www.boliveira.com/NAMD.html

I am confuse because if the values of the backward and foward transformation should have opposite sign of course they will never converge.

I feel that I'm missing some step but I can not figure out what...

Excuse me the long post but all my group works with amber/TI and I dont have anyone who can help me.

Can anyone help me in all these doubts??

Any help is highly appreciated...

Thanks in advance

Bruno

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