[gmx-users] Problem in preparation of the enzyme/substrate complex
Tsjerk Wassenaar
tsjerkw at gmail.com
Thu Feb 19 14:39:20 CET 2009
Hi Ji,
The big problem with transition states like these is that you can't
properly describe the tetrahedral intermediate classically; you have
to consider a whole bunch of non-classical interactions with the
environment (the halfway transferred proton from serine to histidine,
for instance). That calls for quantum... (probably way expensive, as
Mark commented).
Tsjerk
On Thu, Feb 19, 2009 at 2:14 PM, Ji Liu <zjuliuji at gmail.com> wrote:
> Hi all,
>
> It's really a transition state of enzyme catalyzed reaction as Tsjerk said.
> Firstly, the hydrogen from serine will bind with the His nearby. Afterwards,
> the serine residue will nucleophilicly bind with substrate to form such a
> tetrahedral intermediate.
> However, i did not attend to explore the whole catalysis process by
> molecular dynamics simulation. Acturally, i expect to get such a system
> stable in transition state. After the equilirium of the system, i can change
> the position of some groups of substrate. At this moment, the substrate can
> be changed to another conformation--another enantiomer, and the free energy
> difference between two state is expected to be calculated by thermodynamic
> intergration. By this way, the tendency of the system changing from one
> state to another one can be parameterized.
> So I guess the biggest trouble i encountered might be the construction of
> such a transition state system and let it run in Gromacs. But I can't work
> with force field parameter as Justin said. Maybe i should take the
> feasibility of my original plan into a good consideration. Anyway, so much
> thanks to you guys. Mark, Tsjerk, Justin and everyone here.
>
> Regards
> Ji
>
> On Thu, Feb 19, 2009 at 8:43 PM, Tsjerk Wassenaar <tsjerkw at gmail.com> wrote:
>>
>> Hi,
>>
>> Even worse, this looks like a transition-state product. The hydrogen
>> originating from the serine will not just have wandered off. It is
>> unlikely that it happened to go sit on the other oxygen. Rather, the
>> other oxygen, which would originally be double-bonded would probably
>> form a strong hydrogen bond with some other residue (histidine?),
>> rendering the carbon exposed enough for a nucleophilic attack by
>> serine, followed by a series of events likely resulting in HO-R' being
>> cut off. You won't be able to properly describe the transition state
>> using classical means only.
>>
>> Cheers,
>>
>> Tsjerk
>>
>> On Thu, Feb 19, 2009 at 1:19 PM, Justin A. Lemkul <jalemkul at vt.edu> wrote:
>> >
>> >
>> > Ji Liu wrote:
>> >>
>> >> Hi Tsjerk,
>> >>
>> >> Sorry i did not supply any information about the enzyme/substrate
>> >> system.
>> >> Here, I'm studying the interaction between ester (substrate) and lipase
>> >> (enzyme). The substrate contains C, O and H atoms. More details are
>> >> shown in
>> >> the following address.
>> >> http://picasaweb.google.com/ZJULiuJi/Experiments#5304476447992943186
>> >> Also I'll check the archives for related topics. Thank you so much.
>> >>
>> >
>> > Based on the structure you've shown, I do not believe there is any easy
>> > solution, other than going through the painstaking progress of deriving
>> > new
>> > force field parameters. It doesn't matter so much which atom types are
>> > used
>> > in your case, but how they are linked. An ester adduct such as you've
>> > shown
>> > has not been parameterized within the Gromacs implementation of
>> > Gromos96.
>> > If other researchers have done it, then your best bet is to see how
>> > they
>> > did it and hopefully apply it to your situation.
>> >
>> > Otherwise, you have a long project ahead of you just to derive the
>> > correct
>> > parameters.
>> >
>> > -Justin
>> >
>> >> Ji
>> >>
>> >> On Thu, Feb 19, 2009 at 6:18 PM, Tsjerk Wassenaar <tsjerkw at gmail.com
>> >> <mailto:tsjerkw at gmail.com>> wrote:
>> >>
>> >> Hi Ji,
>> >>
>> >> Well, if others have been there before, you can of course take from
>> >> their experience. You haven't mentioned the substrate you're dealing
>> >> with, though, so none of us can tell if we can offer the solution to
>> >> your problem. First try to search the user list archives and the
>> >> topology contribution section of the gromacs site. If that doesn't
>> >> give any results, you can post to the user list and see if any of us
>> >> has already been there...
>> >>
>> >> Cheers,
>> >>
>> >> Tsjerk
>> >>
>> >>
>> >> On Thu, Feb 19, 2009 at 10:35 AM, Ji Liu <zjuliuji at gmail.com
>> >> <mailto:zjuliuji at gmail.com>> wrote:
>> >> > Hi Tsjerk,
>> >> >
>> >> > Thanks a lot.
>> >> > Surely I can't modify the force field by my self. It's impossible
>> >> to me to
>> >> > understand all of things you mentioned. So is it the only way to
>> >> achieve my
>> >> > purpose? If so, it's so frustrating. I've been trying my best to
>> >> contact
>> >> > with the author of one of my references. He applied several of
>> >> Gromos 96
>> >> > force field (may be he modified these force field too) to a
>> >> similar
>> >> > enzyme/substrate system, and hope i can get some information from
>> >> him. Even
>> >> > though, i really eager to get some knowledge from all of
>> >> gmx-users. Anyway,
>> >> > I'm always grateful for your comment.
>> >> >
>> >> > Ji
>> >> > On Thu, Feb 19, 2009 at 5:09 PM, Tsjerk Wassenaar
>> >> <tsjerkw at gmail.com <mailto:tsjerkw at gmail.com>> wrote:
>> >> >>
>> >> >> Hi,
>> >> >>
>> >> >> > I'm not familiar with
>> >> >> > i can't tell myself which
>> >> >> > guess i can
>> >> >> > I have no idea whether
>> >> >>
>> >> >> This is the worst possible basis for trying to modify a force
>> >> field.
>> >> >> First get well acquainted with molecular dynamics and the role
>> >> and
>> >> >> whereabouts of force fields. Then you can start thinking of
>> >> using such
>> >> >> knowledge to modify the force field. You will possibly be able
>> >> to
>> >> >> change a force field, but making it produce sensible results is
>> >> a
>> >> >> different thing.
>> >> >>
>> >> >> Sorry for not telling you what you want to hear.
>> >> >>
>> >> >> Tsjerk
>> >> >>
>> >> >> --
>> >> >> Tsjerk A. Wassenaar, Ph.D.
>> >> >> Junior UD (post-doc)
>> >> >> Biomolecular NMR, Bijvoet Center
>> >> >> Utrecht University
>> >> >> Padualaan 8
>> >> >> 3584 CH Utrecht
>> >> >> The Netherlands
>> >> >> P: +31-30-2539931
>> >> >> F: +31-30-2537623
>> >> >> _______________________________________________
>> >> >> gmx-users mailing list gmx-users at gromacs.org
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>> >> >
>> >> >
>> >> > _______________________________________________
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>> >>
>> >>
>> >> --
>> >> Tsjerk A. Wassenaar, Ph.D.
>> >> Junior UD (post-doc)
>> >> Biomolecular NMR, Bijvoet Center
>> >> Utrecht University
>> >> Padualaan 8
>> >> 3584 CH Utrecht
>> >> The Netherlands
>> >> P: +31-30-2539931
>> >> F: +31-30-2537623
>> >> _______________________________________________
>> >> gmx-users mailing list gmx-users at gromacs.org
>> >> <mailto:gmx-users at gromacs.org>
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>> >>
>> >>
>> >>
>> >> ------------------------------------------------------------------------
>> >>
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>> >
>> > --
>> > ========================================
>> >
>> > Justin A. Lemkul
>> > Graduate Research Assistant
>> > Department of Biochemistry
>> > Virginia Tech
>> > Blacksburg, VA
>> > jalemkul[at]vt.edu | (540) 231-9080
>> > http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin
>> >
>> > ========================================
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>>
>>
>>
>> --
>> Tsjerk A. Wassenaar, Ph.D.
>> Junior UD (post-doc)
>> Biomolecular NMR, Bijvoet Center
>> Utrecht University
>> Padualaan 8
>> 3584 CH Utrecht
>> The Netherlands
>> P: +31-30-2539931
>> F: +31-30-2537623
>> _______________________________________________
>> gmx-users mailing list gmx-users at gromacs.org
>> http://www.gromacs.org/mailman/listinfo/gmx-users
>> Please search the archive at http://www.gromacs.org/search before posting!
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>
>
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--
Tsjerk A. Wassenaar, Ph.D.
Junior UD (post-doc)
Biomolecular NMR, Bijvoet Center
Utrecht University
Padualaan 8
3584 CH Utrecht
The Netherlands
P: +31-30-2539931
F: +31-30-2537623
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