Re: Temperature dependent unfolding..

From: Richard Wood (
Date: Thu Sep 06 2007 - 21:55:44 CDT

Hi all, Another thing one has to ask themselves is what is the "physical significance" of a protein folding at 450 K, not to mention 520 K. I hope we do realize that this is way above "physiological" temperatures and is highly unlikely to be "meaningful". At this temperature, does the term "protein folding" really have any significant meaning? This is kind of like the solvated protein MD simulation I ran once at 500 K. It made for some pretty water clustering pictures (some even evaporated!), but the results weren't physically relevant. Richard Richard L. Wood, Ph. D. University of Minnesota Dept. of Medicinal Chemistry, College of Pharmacy 717 Delaware St. SE Minneapolis, MN 55414-2959 ----- Original Message ---- From: Arun Krishnan <> To: Richard Wood <> Cc: Sent: Thursday, September 6, 2007 9:25:54 PM Subject: Re: namd-l: Temperature dependent unfolding.. 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 <> 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 ----- Original Message ---- From: Neema Salimi <> To: Giovanni Settanni <> Cc: 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: >> downloads/min.namd < >> min.namd> >> b) heating to 300K: >> heating.namd >> c) equilibration @300K: >> downloads/equilibrate_300K.namd >> d) production @300K: >> production_300K.namd < >> downloads/production_300K.namd> >> e) heating to 520K: >> heating_to_520K.namd >> f) equilibration @520K: >> downloads/equilibrate_520K.namd >> g) production @520K: >> production_520K.namd < >> 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* < >> <mailto:>> 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. >> > Checked by AVG Free Edition. >> > Version: 7.5.472 / Virus Database: 269.8.0/817 - Release Date: >> 5/24/2007 4:01 PM >> > > > > Neema Salimi University of California-San Francisco Graduate Group in Biophysics Agard Lab Lab Phone: (415) 476-5143 Choose the right car based on your needs. Check out Yahoo! Autos new Car Finder tool. ____________________________________________________________________________________ Park yourself in front of a world of choices in alternative vehicles. Visit the Yahoo! Auto Green Center.

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