Re: free energy methods cheat-sheet/comparison chart

From: Niklaus Johner (
Date: Mon Mar 25 2013 - 16:17:06 CDT

I have tried out several methods for several different problems over the last year, but my experience is still limited. I'll nevertheless give you my opinion. I'll won't consider the alchemical transformations here (FEP, thermodynamic integration,...)

First of all I think SMD has a disadvantage over all the others. Namely if you don't pull slowly enough, you will largely overestimate the force and you won't have any way of increasing the sampling except restarting the simulation with a smaller pulling speed. With most other methods, if your free energy is not converged you can simply continue your simulation.

Now in my experience, using SMD for non-equilibrium simulations and the Jarzynski type of equalities to calculate free energies doesn't work too well. I was calculating the binding free energy of a peptide to a membrane, but the friction of the water on the peptide would lead to large overestimates of the free energy. Better go for a very slow pulling force and very few repeats.

Umbrella sampling seems to be a very safe bet in many cases. The main drawback is when using a CV that is highly degenerate (multiple states for a single value of the CV) and for which the energy barriers to interconvert from one state to the other at that particular value of the CV are large. Then you will basically be highly biased towards the starting structures that you use in each window. Think of the folding of a peptide, described by the radius of gyration for example, where it might be very difficult to interconvert between two distinct folded states without going through an unfolded state (large radius of gyration). In such cases methods like metadynamics or ABF, where you will cross the whole range of the CV many times will be more appropriate.

For ABF and metadynamics, I think that a major difference is that in metadynamics you will mainly sample the low free energy regions, whereas in ABF you will get a more homogeneous sampling of the whole CV space. Metadynamics has the disadvantage of offering (to my knowledge) no real error estimate.
Another method similar to metadynamics but where error estimates are straightforward, and allows for multiple totally independent simulations is "driven adiabatic free energy dynamics". This is nevertheless not available in namd but is included in the plumed plugin.

Hope that helps,


Niklaus Johner
Weill Cornell Medical College
Harel Weinstein Lab
Department of Physiology and Biophysics
1300 York Avenue, Room D-501
New York, NY 10065

On Mar 25, 2013, at 3:56 PM, Thomas C. Bishop wrote:

This is for a molecular dynamics class I'm doing. The question has come
up "What's pro/con of diff methods and which works best when & where."

Aron gave an excellent start.
It would be great for experts to offer input and I"ll try to organize
into something useful.


On 03/25/2013 02:50 PM, JC Gumbart wrote:
What are you trying to calculate specifically?

On Mar 25, 2013, at 2:49 PM, Thomas C. Bishop wrote:

Does anyone happen to have a "cheat-sheet" with the pros and cons of the diff free-energy methods or a review that provides this information.

Thanks in advance,


  Thomas C. Bishop
   Tel: 318-257-5209
   Fax: 318-257-3823<>

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