Hello Thomas,
thanks a lot again for your valuable comments !
Regarding the scaling constant (which "preventively" scale restraints)
when SC pot. are used: 1/lambda versus 1/(1-lambda) maybe it is not
the "full typo" as this is probably dependent on simulated process. For
the ligand "disappearing" scaling constant
is 1/(1-lambda) for the opposite process (appearing) perhaps 1/lambda is
used. This would correspond to the disappearing/appearing
SF-potentials where in case of disappearing multiplicative constant
(1-lambda) is used and in case of appearing it is just lambda.
At the end I would like just to be 100% sure about the technical
realization (in Amber) of the approach which you suggested.
#1 - appearing of the restraints while ligand is fully (vdw/el)
interacting with receptor during this process
Here I would use this approach:
V0 = Receptor + Ligand (in water)
no restraint is applied in V0 ( ifsc=0, scmask='',crgmask='' )
dvdl_norest=0
V1 = Receptor + Ligand (in water)
Ligand is restrained in V1 with target restraints (defined in the RST
file) (ifsc=0, scmask='',crgmask='')
dvdl_norest=0
So this is sipmle the (i) idea of the linear mixing of the original system
V0 (without restrains) and system V1 (with fully
restrained ligand). With growing lambda V0 is transformed into V1. To be
frank I have no other idea here except maybe the (ii) idea
of multiple RST_lambda files with growing force constants, in that case
probably V0 and V1 should be identical: Receptor +
restrained ligand.
Regarding to the first (linear mixing) idea (i) I am just confused with
your comment:
-----------------------------------------------------------------------
I) activate restraints without softcore and LINEAR mixing of restraint
strength
-------------------------------------------------------------------------
which suggest that even linear mixing is probably not appropriate here to
introduce smoothly restraints while R fully intercat with L via vdw and
el. potentials.
So please make clear these technical aspects here.
#2 Decoupling (vdw/el) the fully restrained ligand.
Here I would use this setup:
V0 = Receptor + Ligand (in water)
Ligand is restrained in V0 with target restraints (defined in the RST
file) (ifsc=1, scmask=':LIGAND',crgmask='')
dvdl_norest=1
V1 = just Receptor (in water)
( ifsc=1, scmask='',crgmask='' )
dvdl_norest=1
However I am again not sure here as this setup is probably OK from the
point of the decoupling of the ligand but not from the
point of the restraints as the final state of this transformation (V1)
should correspond to noninteracting ligand (vdw/el) but
still present in the system and fully restrained respect to receptor. But
here is also important internal Amber interpretation ...
Anyway the second possibility for V1 might be here:
V1 = Receptor + Ligand (in water) where all the ligand atoms are DUMMY
atoms.
Ligand is restrained in V1 with target restraints (defined in the RST
file) (ifsc=1, scmask=':LIGAND' or scmask='' ???, crgmask='')
dvdl_norest=1
So please clarify also this point.
Once again thanks a lot for your help !
Best wishes,
Marek
Dne Tue, 08 May 2012 18:40:14 +0200 <steinbrt.rci.rutgers.edu> napsal/-a:
> Hi,
>
>> a)
>> "restraints are divided by lambda" which is not in agreement with my
>> just
>> commented experience from which is clear that the restraints are divided
>> by (1-lambda).
>
> yes, that seems to be a typo, divided by (1-lambda) would be more
> correct.
>
>> b)
>> The scaling of the restraints (that reported in output files) is
>> present
>> probably just in case of usage of softcore potentials not in the case
>> when
>> the softcore potentials are not used
>> and just simply linear mixing is used instead. Am I right ?
>
> that is right. The two steps envisioned are
>
> I) activate restraints without softcore and linear mixing of restraint
> strength
>
> II) keep restraints intact (by scaling) and switch of the ligand (using
> softcore)
>
>> -------------------------------------------------------
>> Scaling up weight of 20.000 by 2.000
>> New weight 40.000
>> --------------------------------------------------------
>>
>> is really just informative and the final restraint applied to the ligand
>> will be still original value of 20 in this case. Am I right ?
>
> Correct, this is what the scaling message tries to say (maybe it could be
> a bit better worded, though...)
>
>> If this is true, the first step of the decoupling of the restrained
>> ligand:
>>
>> dA*
>> (RL)s -----> (R)s***(L)v
>>
>> (i.e. gradually turn on restraints while el./vdw interactions are
>> simultaneously gradually turned off using softcore potentials)
>>
>>
>> of the whole process
>>
>>
>> dA* dAr
>> (RL)s -----> (R)s***(L)v----->(R)s + (L)v (1)
>>
>>
>> might be in principle realised in one Amber TI step by providing for
>> each
>> lambda different RST file (let say RST_lambda) where I use
>> different values of force constants in each RST_lambda (i.e. smoothly
>> growing with increasing lambda in my particular case).
>
> in principle yes, in practice no, due to two problems: First, I do not
> know how sampling will be affected by simultaneously turning on
> restraints
> and turning off interactions, this would need to be carefully tested. The
> second point is technical. Since the ligand is present only in V0,
> restraints can be defined in V0 only. In this case they can either be not
> counted in dvdl (thats what dvdl_norest does) or they count as restraints
> being removed, since they are not present in V1 anymore. What you would
> want, however is to count restraints as appearing while the ligand is
> disappearing, something that Amber is not set up to do. You could
> subtract
> the restraint contribution times two from the resulting dvdl by hand, but
> would need to carefully check that this really covers all energy
> contributions.
>
>> (dAa*, dAb*). It seems to me (if I understood everything well) that you
>> agree here with me just for the substep "dAa*" and in case of
>> "dAb*-step" (gradual vanishing of vdw/el interactions of the fully
>> restrained ligand) you suggest dvdl_norest=1.
>
> dvdl_norest should only be switched on during the second, ligand
> decoupling step. Turning it on in the first step defeats the purpose of
> that step which is to calculate the dG-contribution of adding the
> restraints. Also, since the first step does not turn on ifsc, you should
> not be able to set dvdl_norest=1.
>
>
> There is no problem with such long mails, Marek and I try to answer them
> if I have time and believe that I understand the tricky points myself. I
> still hope that running it over the list will hopefully inform a few
> people more than it confuses ;-)
>
> Kind Regards,
>
> Thomas
>
> Dr. Thomas Steinbrecher
> formerly at the
> BioMaps Institute
> Rutgers University
> 610 Taylor Rd.
> Piscataway, NJ 08854
>
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Received on Wed May 09 2012 - 08:00:02 PDT
