Re: Temperature dependent unfolding..

From: Arun Krishnan (krishnan_at_ttck.keio.ac.jp)
Date: Thu Sep 06 2007 - 20:25:54 CDT

Thanks to all for your suggestions/comments. I am a little confused though.
Since the Phys Rev. paper claimed to see significant unfolding (> 12
Angstroms) for simulations at 450 and 520K, they either used a higher
pressure or something else. Does this mean that unfolding simulations, in
general, are not to be trusted? I have seen papers where there is pretty
good fit between experimental and simulated conformations for the transition
state etc. Just curious to know what kind of results others have obtained
here.

Also, in a paper which compares thermal unfolding with mechanical unfolding
(such as is given in the NAMD tutorial), there seem to be significant
differences in the unfolding pathway for the two methods..

All very confusing!!

Cheers,

Arun

On 9/7/07, Richard Wood <rwoodphd_at_yahoo.com> wrote:
>
> As I pointed out to Giovanni earlier, as much as we'd like to be able to,
> sometimes we can't simulate accurately such processes, as sometimes there is
> a limit as to how we can model the physics of certain situations (i.e, the
> diffusion of lipids in a membrane, or the flow of water over a crystal
> surface of cellulose, two things I've simulated that wound up having
> "supersonic" velocities), due to the limitations of the code.
>
> I personally wouldn't put too much stock in someone trying to compute the
> unfolding of proteins at this point in time.
>
> Richard
>
> Richard L. Wood, Ph. D.
> University of Minnesota
> Dept. of Medicinal Chemistry,
> College of Pharmacy
> 717 Delaware St. SE
> Minneapolis, MN 55414-2959
> rwoodphd_at_yahoo.com<https://mail.google.com/mail?view=cm&tf=0&to=rwoodphd@yahoo.com>
>
>
>
> ----- Original Message ----
> From: Neema Salimi <nsalimi_at_msg.ucsf.edu<https://mail.google.com/mail?view=cm&tf=0&to=nsalimi@msg.ucsf.edu>
> >
> To: Giovanni Settanni <gs_at_mrc-lmb.cam.ac.uk<https://mail.google.com/mail?view=cm&tf=0&to=gs@mrc-lmb.cam.ac.uk>
> >
> Cc: namd-l_at_ks.uiuc.edu<https://mail.google.com/mail?view=cm&tf=0&to=namd-l@ks.uiuc.edu>
> Sent: Thursday, September 6, 2007 12:45:22 PM
> Subject: Re: namd-l: Temperature dependent unfolding..
>
> Extrapolations from room temperature (or slightly higher) are pretty
> worthless for simulations at these temperatures. I've had proteins
> bigger than ubiquitin that unfold far slower at room temperature that
> unfold just fine at 500K. And extrapolations based on (delta)Cp are
> equally meaningless, as for some of the proteins I've looked at, says
> they would unfold in less than 1 picosecond, obviously quite impossible.
>
> On Sep 6, 2007, at 4:34 AM, Giovanni Settanni wrote:
>
> > Hi Arun,
> >
> > did you (very very roughly) check the expected unfolding time of
> > ubiquitin at high temperature extrapolating the Arrhenius's law
> > (with the brutal assumption that there are no solvent phase
> > transitions as you would not see them in the simulations)? It may
> > be much larger than
> > 12ns, and your simulations may be correct (even if they provide no
> > information about the unfolding pathways!). Ubiquitin has a very small
> > unfolding rate at 300K (0.001 s-1), I do not expect it to increase by
> > almost 12 orders of magnitudes with temperature alone. The authors
> > of the phys rev E probably did a temperature AND pressure induced
> > unfolding.
> > Cheers
> >
> > Gianni
> >
> > --
> > Giovanni Settanni
> > Centre for Protein Engineering
> > MRC Centre
> > Hills Road,
> > Cambridge, UK
> > CB2 0QH
> > Phone: +44 1223 402133
> > Fax: +44 1223 402140
> >
> >
> > Arun Krishnan wrote:
> >> Hi Monika,
> >> I have uploaded all my config files to my website. You can get
> >> them from here:
> >> a) energy minimization: http://www.iab.keio.ac.jp/~krishnan/>
> >> downloads/min.namd <
http://www.iab.keio.ac.jp/~krishnan/downloads/>
> >> min.namd>
> >> b) heating to 300K:
http://www.iab.keio.ac.jp/~krishnan/downloads/>
> >> heating.namd
> >> c) equilibration @300K:
http://www.iab.keio.ac.jp/~krishnan/>
> >> downloads/equilibrate_300K.namd
> >> d) production @300K:
http://www.iab.keio.ac.jp/~krishnan/downloads/>
> >> production_300K.namd <
http://www.iab.keio.ac.jp/~krishnan/>
> >> downloads/production_300K.namd>
> >> e) heating to 520K:
http://www.iab.keio.ac.jp/~krishnan/downloads/>
> >> heating_to_520K.namd
> >> f) equilibration @520K:
http://www.iab.keio.ac.jp/~krishnan/>
> >> downloads/equilibrate_520K.namd
> >> g) production @520K:
http://www.iab.keio.ac.jp/~krishnan/downloads/>
> >> production_520K.namd <
http://www.iab.keio.ac.jp/~krishnan/>
> >> downloads/production_520K.namd>
> >> I ran these under NPT.. so some of the comments in the files might
> >> not make sense. (These were put in when I was initially doing an
> >> NVT ensemble).
> >> Do let me know if you see anything wrong.
> >> Thanks in advance.
> >> Cheers,
> >> Arun
> >> On 9/5/07, *Monika Sharma* <
mon_sharma_at_research.iiit.ac.in<https://mail.google.com/mail?view=cm&tf=0&to=mon_sharma@research.iiit.ac.in>
>
> >> <mailto:mon_sharma_at_research.iiit.ac.in<https://mail.google.com/mail?view=cm&tf=0&to=mon_sharma@research.iiit.ac.in>>>
> wrote:
> >> hii!!
> >> can you just write your conf file here the last part of the
> >> run?There
> >> might be some problem in going from 300K to 500K.
> >> regards,
> >> monika
> >> Arun Krishnan wrote:
> >> > Dear NAMD list users,
> >> >
> >> > I have been trying to carry out unfolding simulations of
> >> Ubqiuitin. I
> >> > use the top_all22_prot.inp and par_all22_prot.inp topology and
> >> > parameter files.
> >> > I did the following steps:
> >> >
> >> > a) Energy minimization
> >> > b) Heating to 300K
> >> > c) Equilibration for 50ps NPT
> >> > d) Production run @300K for 1ns. NPT
> >> > e) Heating to 500K
> >> > f) Equilibration for 50ps NPT
> >> > g Production run @500K for 12ns NPT
> >> >
> >> > Very surprisingly, I don't see the RMSD values changing
> >> (with respect
> >> > to the final equilibrated frame at 300K) by greater than 4-5
> >> > Angstroms. This is very weird. There is a paper in Physical
> >> Review E,
> >> > 72, 051928, 2005 "Unfolding dynamics of the protein ubiquitin:
> >> Insight
> >> > from simulation" where they achieved drastic unfolding
> >> within 1ns
> >> > for ubiquitin at 520K. I followed what they did and tried
> >> at 520K
> >> too.
> >> >
> >> > I have used NPT throughout.. but I also used NVT and NVE
> >> ensembles..
> >> > and in all cases it seems to be very stable. Does anyone
> >> have any
> >> > pointers to what I might be doing wrong?
> >> >
> >> > Thanks in Advance,
> >> >
> >> > Arun
> >> > -
> >> >
> >>
> >> ---------------------------------------------------------------------
> >> ---
> >> >
> >> > Internal Virus Database is out-of-date.
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> >> 5/24/2007 4:01 PM
> >> >
> >
> >
> >
>
> Neema Salimi
> nsalimi_at_msg.ucsf.edu<https://mail.google.com/mail?view=cm&tf=0&to=nsalimi@msg.ucsf.edu>
>
> University of California-San Francisco
> Graduate Group in Biophysics
> Agard Lab
> http://msg.ucsf.edu/agard/
> Lab Phone: (415) 476-5143
>
>
>
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