Re: new NAMD user ABF setup question

From: Jérôme Hénin (jhenin_at_ifr88.cnrs-mrs.fr)
Date: Sat May 29 2010 - 05:06:50 CDT

Hi Elio,

My guess is that a COM-COM distance will not work well for
peptide/protein binding for any other method than irreversible
unbinding by SMD (which will not give you binding free energies except
on a qualitative level for comparison purposes).

In general, binding free energies are best calculated by alchemical
means (see the alchemical free energy tutorials).

Jerome

On 28 May 2010 16:03, Giacomo Fiorin <giacomo.fiorin_at_temple.edu> wrote:
> Not exactly.  ABF and umbrella sampling can be applied in theory on the very
> same (reaction) coordinates.  The reason why you needed to define a specific
> direction for pulling apart the two proteins was (I think) because of the
> way the Gromacs implementation was written, not the general umbrella
> sampling method.
>
> In the ABF implementation in NAMD, you can try first the COM-COM distance,
> and maybe switch later to more sophisticated ones if you think there is the
> need for.  Also, since it's implemented within the colvars module, you can
> even reuse the exact same variables/coordinates with ABF and umbrella
> sampling, and be able to compare their results, if that's what you are
> interested in.
>
> Giacomo
>
> ---- ----
>  Dr. Giacomo Fiorin
>  ICMS - Institute for Computational Molecular Science - Temple University
>  1900 N 12 th Street, Philadelphia, PA 19122
>  giacomo.fiorin_at_temple.edu
> ---- ----
>
>
>
> On Fri, May 28, 2010 at 8:48 AM, Elio Cino <ecino_at_uwo.ca> wrote:
>>
>> Thanks Giacomo. Very helpful reply. I think that I am treating the ABF
>> setup too much like that for umbrella sampling where a specific coordinate
>> is define. For ABF if I simply specify a range of COMdistance between the
>> protein and ligand then I presume that conformations in this defined COM
>> range will eventually be sampled. This way I do not need to pull them apart
>> along a straight line, for example. Hopefully I have this straight. Ill have
>> to read a bit more on ABF to be sure. Thanks again.
>>
>> ----- Original Message -----
>> From: Giacomo Fiorin <giacomo.fiorin_at_gmail.com>
>> Date: Thursday, May 27, 2010 5:27 pm
>> Subject: Re: namd-l: new NAMD user ABF setup question
>> To: Elio Cino <ecino_at_uwo.ca>
>> Cc: namd-l_at_ks.uiuc.edu
>>
>> > Hi Elio, the most intuitive collective variable, or reaction coordinate
>> > is the COM-COM distance, whichever its direction may be.  If you want to
>> > pull them apart (and back together!) along a specific direction, you have to
>> > restrict the variable to be on the projection along that "specific
>> > coordinate" as you said: do you mean Cartesian coordinate (x, y or z)?  My
>> > suggestion is to use distanceZ from the ABF implementation in NAMD 2.7b1 and
>> > 2.7b2, and also define distanceXY with a restraint to be zero, so that
>> > you'll have a straight line, if that's what you want.
>> >
>> > The comment you were referring to sounds specific to a well defined
>> > system, which may not be similar to yours.  The boundaries defining the
>> > relevant region of your system are your choice entirely.
>> >
>> > You should check out the ABF paper and compare it with umbrella sampling
>> > using your own intuition.  Too often comparisons between free energy methods
>> > are based on specific examples that may not necessarily be applicable to
>> > your case.
>> >
>> > In any case, when the variables are appropriately chosen, ABF DOES give
>> > you an accurate PMF within the range (boundaries) you defined.
>> >
>> > Giacomo
>> >
>> > ---- ----
>> >  Dr. Giacomo Fiorin
>> >  ICMS - Institute for Computational Molecular Science - Temple
>> > University
>> >  1900 N 12 th Street, Philadelphia, PA 19122
>> >  giacomo.fiorin_at_temple.edu
>> > ---- ----
>> >
>> >
>> >
>> > On Thu, May 27, 2010 at 3:10 PM, Elio Cino <ecino_at_uwo.ca> wrote:
>>>
>>> > Hello. I have been trying to calculate free energies of peptide binding
>>> > to a protein with umbrella sampling in gromacs with mixed results. Anyways,
>>> > I was hoping the ABF method may help me get accurate results faster than
>>> > umbrella sampling. I have read some of the ABF tutorial and manual, but am a
>>> > bit confused about the ABF setup. I set the boundaries for the COM distance
>>> > between the peptide and protein, but I think I need to specify a direction
>>> > also since I want to pull the peptide away from the protein along a specific
>>> > coordinate. I am unsure if they is correct, and if so how to specify the
>>> > direction. Also, I read a comment saying that much of the ABF calculation
>>> > time is spent climbing uphill to overcome the forces (between peptide and
>>> > protein) at low COM distances and to avoid this, the lower boundary should
>>> > be increased. Will this still provide an accurate PMF? It seems that
>>> > excluding these low boundary states would cause some errors in the delta G.
>>> > Any help is appreciated. Thanks.
>>> >
>>> > Elio Cino
>>
>> >
>>
>>
>> Elio Cino
>
>

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