Dear Carlos,
Can I use TI for absolute binding free energy? I thought TI will be
useful only for calculating the relative binding free energy for two
ligands? If I want to calculate absoulte binding free energy, what
should be the second ligand.Should I use all atoms as dummy?
Rajesh
On Thu, 10 Mar 2011 12:47:45 -0500
Carlos Simmerling <carlos.simmerling.gmail.com> wrote:
> are you trying to calculate teh absolute binding free energy? there
>is lots
> of work on this in the literature that you should read, it can be
>much more
> difficult than relative affinities.
> On Thu, Mar 10, 2011 at 12:45 PM, Rajesh Raju <
> rajesh.raju.mail.chem.tamu.edu> wrote:
>
>> I have never used TI or FEP. I thought I can use umbrella sampling
>> method to generate PMF profile and calculate the binding free
>>energy.
>> TI, we must have two ligand and we can calculate the relative free
>> energy?
>>
>> Can I use TI for calculating the binding free energy for the single
>> solute?
>>
>> Thanks
>> Rajesh
>>
>>
>> On Thu, 10 Mar 2011 09:45:41 -0500
>> Carlos Simmerling <carlos.simmerling.gmail.com> wrote:
>> > it still isn't clear what you want to do. why use umbrella
>>sampling
>> >for
>> > this, instead of TI or FEP?
>> >
>> > On Wed, Mar 9, 2011 at 1:55 PM, Rajesh Raju
>> > <rajesh.raju.mail.chem.tamu.edu>wrote:
>> >
>> >> Dear Carlos,
>> >>
>> >> Thank you very much for your reply. I have attached the receptor
>> >>molecule
>> >> structure with this email. I would like to studnt binding free
>> >>energy of
>> >> small solutes like benzene. I have shown the reaction coordinate.
>>I
>> >>want to
>> >> generate aPMF profile for the inclusion of the solute molecules
>>into
>> >>this
>> >> receptor. I can do the umbrella sampling in two different ways.
>>One
>> >>way is
>> >> to make the coordinate and tolopoly files for different distance
>> >>restraint
>> >> and do umbrella sampling. The advantage is the dist_vs_time value
>> >>will start
>> >> from the closet value correspond to the distant constraint value.
>> >>Second way
>> >> is to keep the solute and receptor molecules at same
>>configuration
>> >>and do
>> >> individual simulations corresponding to the different distance
>> >>constraint
>> >> value. Would both give the same PMF profile ? If different why
>>and
>> >>which is
>> >> the best approach?
>> >>
>> >> Thanking you in advance
>> >> Rajesh
>> >>
>> >>
>> >>
>> >>
>> >> On Wed, 9 Mar 2011 07:04:24 -0500
>> >> Carlos Simmerling <carlos.simmerling.gmail.com> wrote:
>> >>
>> >>> you haven't made it clear what you're trying to calculate. Are
>>you
>> >>> following
>> >>> a procedure shown to work well in a peer-reviewed article? I
>>suspect
>> >>>that
>> >>> what you want to do is quite challenging. Keep in mind that
>>umbrella
>> >>> sampling works well ONLY if the reaction coordinate you choose
>>is
>> >>>the one
>> >>> responsible for the relevant energy changes, and you must be
>>able to
>> >>>fully
>> >>> sample over motions in all of the other degrees of freedom in
>>each
>> >>>of the
>> >>> umbrella windows. I suspect that at a fixed distance you will
>>find
>> >>>it
>> >>> difficult to properly sample over all other motions (such as
>>side
>> >>>chains,
>> >>> ligand flexibility, etc.
>> >>>
>> >>> given that, I'm not sure quite what you're asking. It seems that
>>you
>> >>>have
>> >>> different numbers of waters. you can adjust the water buffer
>>length
>> >>>in
>> >>> leap
>> >>> when you build the molecule- it might require trial and error.
>> >>>
>> >>> during your umbrella runs, make sure that you have overlap in
>>the
>> >>> distribution of distances (histogram them) between all
>>neighboring
>> >>> windows.
>> >>> any gaps will result in errors in free energy profile.
>> >>>
>> >>>
>> >>>
>> >>> On Tue, Mar 8, 2011 at 6:21 PM, Rajesh Raju
>> >>> <rajesh.raju.mail.chem.tamu.edu>wrote:
>> >>>
>> >>> Dear Amber users,
>> >>>>
>> >>>> I am planning to do an umbrella sampling on one of the receptor
>> >>>> molecule. I used the distance between the center of masses of
>>the
>> >>>> receptor and ligand molecule as constraint. My doubts are:
>> >>>>
>> >>>> [1] Do I need to make different coordinate files for the
>>complex,
>> >>>> corresponding to the distance between the center of masses of
>>the
>> >>>>two
>> >>>> molecules? or Can I use the same coordinate file for all
>>individual
>> >>>> simulations of the different windows?
>> >>>>
>> >>>> [2] changing the distance variable in the 'DISANG=dist.dat'
>>file to
>> >>>> different distance values corresponding to different windows,
>>and
>> >>>>keep
>> >>>> the same coordinate files with center of masses of two
>>molecules
>> >>>>close
>> >>>> to zero, would be the same effect as that of the doing
>>different
>> >>>> window simulations, making new coord files corresponding to the
>> >>>> umbrella sampling distance.
>> >>>>
>> >>>> So far I proceeded with the second approach:
>> >>>>
>> >>>> I made the new coordinates corresponding to different R
>>variables
>> >>>>from
>> >>>> 0.5 to 10 ..20 windows. and made parameter and coordinate files
>>for
>> >>>> the individual windows..The number of water molecules are
>>slightly
>> >>>> different....
>> >>>>
>> >>>> Which is the best way?
>> >>>>
>> >>>> Thanks
>> >>>> Rajesh
>> >>>>
>> >>>> _______________________________________________
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>> >>>>
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>> >>
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Received on Thu Mar 10 2011 - 10:30:02 PST
