SV: Re: [gmx-users] number of lambda values

[Soren Enemark]

 Hi David,
 First, thank you very much for your elaborate answer to my question.
 Your fast response has given me a little time to think about the info
 you supplied.
  
Quoting David Mobley <dmobley at gmail.com>:
  > Soren,
> 
> >  Given a certain amount of time and computer power available, is it better
> > in general to do short simulations for many lambda values or to do long
> > simulations for fewer lambda values?
> 
> This is a really good question, and one that is hard to answer
> generally (that is, the answer is probably somewhat system-dependent).
> Here are a couple considerations:
> 
> 1) You need enough lambda values to ensure good phase space overlap
> from one lambda value to the next, otherwise the results you get will
> be meaningless (all of the FEP/TI type expressions require sufficient
> overlap between the  Hamiltonians of interest).
   
   So if I understand correctly, there is no way, apart from from the indirect 
 method you describe below, that can say how big a part of the sampled 
 configurations that overlap?
   
  > Bennett Acceptance
> Ratio (a type of FEP) is somewhat more efficient and may require
> slightly fewer lambda values. It is probably nontrivial to figure out
> how many lambda values is "enough", either. The approach I would
> typically take for a particular problem is to start with lots of
> lambda values for a "typical" problem of that type, and compute the
> "correct" answer, and then reduce the number of lambda values until
> the answer starts to deteriorate, then add a couple back in and use
> that number.
> 2) Regardless of whether you have enough lambda values, if your
> simulations are not long enough, your results will be meaningless.
> Your simulations should probably be at least 10x the typical
> correlation time for your system (for your observable of interest).
> For example, if you are calculating binding free energies of a ligand,
> and the ligand has two different sub-conformations it can occupy in
> the binding site, and the timescale for switching between these is 100
> ps, you would need to run at least 1 ns at each lambda value to ensure
> you have time to sample each conformation a sufficient number of
> times. In the extreme case, suppose you started with only one of these
> conformations and ran 50 ps, observing no swaps -- instead of
> computing the binding free energy of the ligand, you would compute
> what the binding free energy would have been if the ligand could only
> occupy one conformation in the binding site. This could be not at all
> related to the correct binding free energy.
> 
> Anyway, that all basically boils down to this: If the transformation
> you are doing is "hard" (like turning off LJ interactions for some
> atoms in your system), (1) dictates that you will need a relatively
> large number of lambda values, since the phase space changes a great
> deal,
   
   What is it that makes the phase space change a great deal for a "hard"
 transformation? (And why do you consider it particularly "hard"?)
 In other words, why would turning of LJ interactions be more difficult than
 other transformations? And, forgive my ignorance which other kinds of
 transformations could such other transformations be?
 
 All the best regards, and thank you again for enlighting me on this,
 -Søren
   
  > and if the system you are looking at has long correlation times,
> (2) dictates that you will need long simulations. You need to do some
> investigation to see what your problem is like. I would especially
> recommend looking at correlation times. Maybe run out one or two
> really long MD trajectories to get an idea of some of the relevant
> timescales in your system.
> 
> I would also recommend not thinking of it so much as an optimization
> problem of, "How do I best use X amount of computer time?" but, "How
> much computer time will I have to spend where to get my statistical
> uncertainty down to X in the most efficient way?" Depending on your
> system, (1) and (2) may dictate that the amount of computer time you
> need to spend is more than you actually want to spend. Then you have
> to decide, basically, how big of error bars you are willing to
> tolerate.
> 
> David Mobley
> UCSF
> >
> >  Thanks for all the good advices on the list,
> >  Soren
> >
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