Adrian,
please excuse the late response. I wish a belated happy new year & merry
christmas and am grateful for your comments :-) I will get back to you
when I have more specific questions in the future.
Jan-Philip
On 12/20/2011 07:18 PM, Adrian Roitberg wrote:
> Hi Jan-Philip
>
> Wow, you are expecting a web site to be up to date ! ;-)
>
> Sorry about that...
>
>
> We have a couple of papers under review regarding changes in
> conformation coupled to pH changes. This is an interesting area, and we
> are finding it to be quite challenging and not clear in the field at all.
>
> Basically, when you have two different conformations whose equilibrium
> depends on pH, then the pKa for the important residues in each
> conformation MUST be different. Hence, while you can measure a 'pKa' as
> the midpoint in a titration curve, that result is most likely a sign of
> the conformational transition and NOT of the protonation change.
>
> We have succeeded in seeing things like you mention by running MD at
> constant pH for a pH where a dimer is stable. Then we 'jump' the pH to a
> value where it is unstable, and you see changes. We have seen this in
> the ~50 ns MD range, with implicit solvent.
>
> You do not see a full unbinding of the dimer, but you clearly see
> instabilities.
>
> The 'correct' way to do this is to do umbrella sampling for instance
> versus monomer separation, using the protonation states at both pHs. You
> should see two very different profiles in that case, but it is a lot of
> work.
>
> As for the replica pH, etc, we will have it all released for Amber12,
> and it will have BOTH temperature replicas (with each replica at the
> same constant pH) AND tru ph-replica, where each replica has a different pH.
>
> Contact me directly if you have more questions pelase.
>
> Adrian
>
>
>
>
>
> On 12/20/11 11:15 AM, Jan-Philip Gehrcke wrote:
>> Hey,
>>
>> I have read the section about constant pH MD in the manual as well as
>> for example
>>
>> "Constant pH Replica Exchange Molecular Dynamics in Biomolecules Using a
>> Discrete Protonation Model" by Weng, Roitberg (J. Chem. Theory Comput.,
>> 2010, 6 (4), pp 1401–1412)
>>
>> That paper closes with
>>
>> "our future work will include studies of pH-dependent protein dynamics
>> and application of this constant pH REMD to large proteins"
>>
>> Is any of this "future work" already published?
>> http://www.clas.ufl.edu/users/roitberg/research.htm unfortunately is not
>> up to date :)
>>
>> I'm currently studying a homodimeric protein, each monomer containing
>> about 160 amino acids. What particularly interests me is analyzing the
>> stability of this dimer in dependence of the solution pH. The dream is
>> to "see" when it starts dissociating while decreasing pH.
>>
>> I would be very happy to receive some scientific advise with respect to
>> tackling this problem using molecular dynamics. Do you think that an
>> MD-based study of this problem scientifically makes sense at all? If
>> yes, which method would you use?
>>
>> From the literature I've read, it seems that I will have to stick to
>> implicit solvent approaches. The simplest way would be to use the Mongan
>> et al approach (as currently implemented in Amber) during (very long)
>> classical MD simulations. How long must "very long" be in this case in
>> order to achieve proper conformational sampling? If I have to use REMD
>> -- Adrian, how severe have the technical challenges been to implement
>> the protonation state exchange scheme you've used in the paper mentioned
>> above?
>>
>> As this particular problem is a side project of mine, honestly, I would
>> very much like to be able to use the best protocol that is already
>> implemented. Basically, I am wondering if such a protocol exists for my
>> problem. If this is not the case, I am very much interested in
>> discussing the difficulties.
>>
>> Thanks for your advise,
>>
>> Jan-Philip
>>
>>
>
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Received on Tue Jan 03 2012 - 08:00:03 PST
