AMBER Archive (2007)

Subject: Re: AMBER: Rate of Dissociation

From: wang (c00jsw00_at_nchc.org.tw)
Date: Sun May 06 2007 - 20:44:36 CDT

Dear all ,
Please , refered to the paper "Biophysical Journal volume 84 march 2003
1493-1506"

wang

Catein Catherine ´£¨ì:

> Dear Sean,
>
> Thank you very much for your help! May I ask you in more details
> regarding the MM-PBSA approach? I used MM-PBSA approach (listed in
> Tutorial 3 of amber webpage) to calculate the gibb free energy for the
> drug binding to the receptor, i.e. calculate the molecular dynamics
> for drug-receptor complex in their binding coordinate and use EXDI=80.0.
>
> Regarding to the approach you suggested below to calculate the rate
> constant, I could use the same approach, but I should do the molecular
> dynamic calculation for the drug-receptor complex in their activated
> state, and use EXDI=saturated drug condition. Did I misunderstand
> anything here?
>
> Do you mind to give me some hints where and how can we find the
> activated state for a dissociating complexes and EXDI for a saturated
> solutions?
>
> Best regards and many thanks!
>
> Cat
>
>
>> From: Sean Rathlef <sean_at_syncitium.net>
>> Reply-To: amber_at_scripps.edu
>> To: amber_at_scripps.edu
>> Subject: Re: AMBER: Rate of Dissociation
>> Date: Fri, 04 May 2007 11:15:03 -0800
>>
>> We tried computing the energy barrier for association / dissociation
>> of a
>> ligand from an receptor using steered molecular dynamics simulations,
>> thus
>> taking into account the conformational changes of the protein, but this
>> method proved to be computationally cumbersome and not very accurate.
>>
>> You should be able to compute a first order rate constant for LR -->
>> L + R
>> via MMPBSA, but you will need to reproduce the energy barrier of L-R*
>> via
>> modeling the system at infinate saturation of L. If you model at
>> infinite
>> L, then you are modeling the energy of that dissociation barrier. To do
>> this via simulation using an implicit solvent, you will have to model
>> your
>> baseline LR structure (i.e., the structure of LR in water), but
>> change the
>> dielectric of your water (78.4) to that of your ligand / drug.
>>
>> Sean
>>
>> ----- Original Message -----
>> From: "David Mobley" <dmobley_at_gmail.com>
>> To: <amber_at_scripps.edu>
>> Sent: Friday, May 04, 2007 9:41 AM
>> Subject: Re: AMBER: Rate of Dissociation
>>
>>
>> > So, you ARE after the rate?
>> >
>> > That sounds like a hard problem. You should probably review the
>> > literature on calculating protein folding rates, as what you're asking
>> > is related to the question of how one would calculate a protein
>> > folding rate from a simulation.
>> >
>> > David
>> >
>> > On 5/4/07, Catein Catherine <askamber23_at_hotmail.com> wrote:
>> > > Dear All,
>> > >
>> > > Could you please kindly give me some hints if I could calculate
>> the rate
>> of
>> > > dissociation of a drug from the receptor protein with AMBER
>> package? If
>> > > yes, what is the best way to do so?
>> > >
>> > > Best regards and many thanks!
>> > >
>> > > Cat
>> > >
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>
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