Dear Adrian and Jerome,
Thank you very much for your comments.
Yes. I am sorry that I did not make it clear and using confusing terminology here.
Yes, experimentally we measured the drug binding and drug removal rate. They are different by 2 order of magnitude (Rate of drug binding > rate of drug removal). So, as we expected to see that the activation energy of the drug binding process is lower than that of drug removal process.
Theoretically, we did a PMF calculation using umbrella sampling method. As we cannot experimentally define the drug binding or drug removal pathways. We have to define the pathway as the distance (r) between the drug and the receptor. We separate the windows from r = 1 to 40 A. As no matter it is binding or removal status, the window defined by r must be the same. I got single PMF profile using this method for binding and removal pathways.
According to Jerome's comment, I should get the same PMF profile if I use steered MD, as far as I also define the pathway as the distance r. Yes, I understand now. Thanks.
I agree with Adrian that I the absolute rate cannot be determined by these method.
If it is possible, may I ask Adrian to give me some more advice on "has to to with friction". Based on my results on umbrella sampling, I found the activation energy is quite small. When you mean "has to do with friction", what is this mean?
If I am only interested to investigate the RELATIVE rate of drug binding process vs the drug removal process. Are there any other methods I should use? If you comes across the use of PMF calculations to determine drug binding and drug removal process (on relative rate), could you pls kindly give me some hints or quote me a references?
Best regards and many thankssssss again for your help.
Cat
> Date: Thu, 20 May 2010 15:41:36 -0400
> From: roitberg.qtp.ufl.edu
> To: amber.ambermd.org
> Subject: Re: [AMBER] umbrella sampling method or steered MD should be used?
>
> Just a general comment because I think we are using confusing
> terminology in this thread.
>
> While Cat initially wrote about PMF being different for the bound and
> unbound state. She is correct ! The PMF is basically the free energy of
> ONE state. Now, when we say that the PMF must be the same for binding
> and unbinding, we are actually forgetting a word in the sentence, which
> we usually omit. What we meant is that the PMF profile (the free energy
> profile) vs distance should be the same.
>
> This is a simple nomenclature issue: using SMD or US we compute free
> energy profiles, and we look at the end points to 'read' free energy
> differences.
>
> As for using barriers for kinetics. There are two VERY important
> problems you will encounter:
>
> 1. Many binding events are barrierless in a free energy profile, but
> still have a rate. This is a non-trivial issue in kinetic theory, and it
> has to do with friction, which terms you include in your calculations, etc.
>
> 2. Going from a barrier to a rate is HARD. I am in the extreme position
> of saying that it is not only hard, it is impossible in most cases,
> because you do not know the prefactor in front of the exponential term
> that has the free energy in it. Transition state theory in its simple
> form (prefactor = kbT/h) is not even a close approximation.
> Assuming that the prefactor is the same vs mutations and looking at
> relative rates is much more reliable.
>
> Adrian
>
>
> On 5/20/10 5:58 AM, Jerome Golebiowski wrote:
> > Yes, you need the activation barrier to estimate your rate.
> > This can be obtained by computing a PMF, either via Umbrella Sampling,
> > SMD, metadynamics, ...
> > You should (must) obtain similar PMF with these methods, provided that
> > you choose the same reaction coordinate approximation (a distance for
> > example). The PMF is a physical quantity and, in principle, does not
> > depend on the way you compute it.
> > We are actually making comparison between US and SMD to study gas
> > diffusions within a protein and we obtain the same PMFs.
> >
> > Jerome
> >
> >
> > On Thu, 2010-05-20 at 17:29 +0800, Catein Catherine wrote:
> >> Hi Jerome and Thomas,
> >>
> >>
> >>
> >> Thanks for your comments. I am interested to study the rate of drug binding and drug removal. To my understanding, it is related to the activation energy of the processes, which is pathway-dependent. Am I correct?
> >>
> >>
> >>
> >> Can I use PMF to calculate the activation energy?
> >>
> >>
> >>
> >> If the answer is yes, should I expect to see the activation energies are different when I use these methods?
> >>
> >>
> >>
> >> If the answer is no, are there any reliable method to calculate activation energy of the drug binding and drug removal process.
> >>
> >>
> >>
> >> Best regards and thanks a lot,
> >>
> >>
> >>
> >> Cat
> >>
> >>> Subject: Re: [AMBER] umbrella sampling method or steered MD should be used?
> >>> From: jerome.golebiowski.unice.fr
> >>> To: amber.ambermd.org
> >>> Date: Thu, 20 May 2010 10:24:54 +0200
> >>>
> >>> As Thomas said, you should see the same PMF for both the forward and the
> >>> backward directions.
> >>> Note that there is a (generally small) difference between the binding
> >>> free energy and the difference between two points of the PMF curve.
> >>> Some authors (including me) consider that the delta(PMF) equals the
> >>> delta(G), but in principle, it's not totally true.
> >>> Best
> >>> Jerome
> >>>
> >>>
> >>> On Thu, 2010-05-20 at 14:27 +0800, Catein Catherine wrote:
> >>>> Dear Sir/Madam,
> >>>>
> >>>>
> >>>>
> >>>> I would like to determine the potential energy changes for drug binding the receptor and for the drug remove from the receptor. In practice, the PMF of binding should be lower than that of removing, otherwise no drug-receptor complex could be formed.
> >>>>
> >>>>
> >>>>
> >>>> I tried to use umbrella sampling method to determine the PMF as a function of distance between the drug and receptor. As the drug removal and drug binding process use the same path (defined as the distance between the drug and the receptor). I can only see PMF for binding and removal are the same.
> >>>>
> >>>>
> >>>>
> >>>> I noted that I can define steered MD by start and end point. Should I expect to see the PMF obtained by binding and removal of drugs are different using these two different SMD restraints?
> >>>>
> >>>>
> >>>>
> >>>> (1)
> >>>>
> >>>> # Change distance between atoms 485 and 134 from 15 A to 20 A
> >>>> &rst iat=485,134, r2=15., rk2 = 5000., r2a=20. /
> >>>>
> >>>>
> >>>> (2)
> >>>>
> >>>> # Change distance between atoms 485 and 134 from 20 A to 15 A
> >>>> &rst iat=485,134, r2=20., rk2 = 5000., r2a=15. /
> >>>>
> >>>> Please kindly help.
> >>>>
> >>>> Cat
> >>>>
> >>>>
> >>>>
> >>>> _________________________________________________________________
> >>>> Hotmail: Trusted email with Microsoft’s powerful SPAM protection.
> >>>> https://signup.live.com/signup.aspx?id=60969
> >>>> _______________________________________________
> >>>> AMBER mailing list
> >>>> AMBER.ambermd.org
> >>>> http://lists.ambermd.org/mailman/listinfo/amber
> >>> --
> >>> Jérôme Golebiowski, PhD (Hab. Dir. Rech.)
> >>> LCMBA, UMR CNRS-UNS 6001
> >>> Molecular Modeling team
> >>> University of Nice Sophia Antipolis, Parc Valrose
> >>> 06108 Nice cedex 2
> >>> http://www.unice.fr/lcmba/golebiowski
> >>> tel +33 (0)4 92 07 61 03
> >>> fax +33 (0)4 92 07 61 25
> >>>
> >>>
> >>> _______________________________________________
> >>> AMBER mailing list
> >>> AMBER.ambermd.org
> >>> http://lists.ambermd.org/mailman/listinfo/amber
> >>
> >> _________________________________________________________________
> >> Your E-mail and More On-the-Go. Get Windows Live Hotmail Free.
> >> https://signup.live.com/signup.aspx?id=60969_______________________________________________
> >> AMBER mailing list
> >> AMBER.ambermd.org
> >> http://lists.ambermd.org/mailman/listinfo/amber
> >>
>
> --
> Dr. Adrian E. Roitberg
> Associate Professor
> Quantum Theory Project
> Department of Chemistry
>
> Senior Editor. Journal of Physical Chemistry
> American Chemical Society
>
> University of Florida PHONE 352 392-6972
> P.O. Box 118435 FAX 352 392-8722
> Gainesville, FL 32611-8435 Email adrian.qtp.ufl.edu
>
> _______________________________________________
> AMBER mailing list
> AMBER.ambermd.org
> http://lists.ambermd.org/mailman/listinfo/amber
_________________________________________________________________
Hotmail: Free, trusted and rich email service.
https://signup.live.com/signup.aspx?id=60969_______________________________________________
AMBER mailing list
AMBER.ambermd.org
http://lists.ambermd.org/mailman/listinfo/amber
Received on Thu May 20 2010 - 16:30:03 PDT
