[gmx-users] LIE method

[Justin Lemkul]

On 5/30/14, 7:50 AM, Mahboobeh Eslami wrote:
> hi
> dear justin
> A few months ago I asked you a question about LIE method.
> According
>   to your guide, i wrote a new .mdp file that didn't use PME (I used RF)
> and used following command for protein-ligand complex? and ligand-sol
> simulations:
> ?mdrun -s newtpr.tpr -rerun full20ns.xtc
> ?then I extract -Elj and -Eqq of ligand in water simulation and use g_lie command.
> But the obtained free energy has great difference with the experimental value.
>
> You
>   told me that i must re-calculate energies from? PME systems, then i
> must take the difference of the energies from another system where the
> same correction hasn't been applied.

That doesn't sound entirely right, but if the discussion happened months ago, 
probably I'm forgetting details.  If you're digging up old conversations, please 
include a link for context.  I discuss a lot of things with a lot of people :)

> Please explain this. How do I do it?

The point is this: you need two energy estimates.  (1) Your ligand bound to the 
protein and (2) the ligand in water.  Using PME is appropriate for doing the 
simulations because the forces will be more accurate.  You then re-evaluate both 
using some other method (long cutoffs, RF, etc) to estimate the interaction 
energy because the PME mesh term cannot be decomposed in a pairwise manner. 
Depending on the size of the molecule, the energy difference is probably small 
in most cases, but may be non-negligible.  Based on these re-evaluated energies, 
you can estimate the binding free energy from LIE.

If the LIE results aren't good, then either (1) the ligand topology is bad or 
(2) the LIE estimate isn't sufficiently rigorous.  Note that LIE neglects 
entropy, so you're assuming that enthalpic terms dominate the interaction; that 
may not always be true.

-Justin

-- 
==================================================

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 601
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalemkul at outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

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