Re: [gmx-users] Open-closed transition in a dimeric enzyme, WTM simulations
Dear Erik, Thanks for the comment. In my case, the closed state of the enzyme is not known (no crystal structure). What do you suggest to check for a better collective variable? I use two CVs with the information of 1. COM-COM distance between the flexible loop and a core part of the one subunit 2. local contacts (CMAP description in plumed) In the simulation trajectories, I see the open-closed transitions several times. Thus, It is showing the event I am searching for. But I am still waiting for the converged FES for the same. Currently, I am trying with a different set of parameters (sigma, hills height). Regards, Tarak On Wed, Jun 15, 2016 at 4:53 PM, Erik Marklund wrote: > Dear Tarak, > > My guess is that your reaction coordinate is ill-chosen and that it fails > to capture some significant transitions in orthogonal directions. This can > be difficult to know beforehand unfortunately. > > Kind regards, > Erik > > > On 10 Jun 2016, at 19:09, tarak karmakar wrote: > > > > Dear All, > > I am studying an enzyme where the closing of a loop should happen upon > > ligand binding to the active site. In unbiased simulations, even after > 300 > > ns of simulation time the loop does not close the reaction center. Thus, > we > > realized that the open-closed conformational change may have a high free > > energy barrier, inaccessible by the unbiased trajectory. Thus, we > performed > > well-tempered metadynamics (WTM) simulations to study that event. > > > > In WTM simulations, we see the opening and closing of the loop almost > five > > to six times within 300 ns time span. The free energy associated with > this > > event has barriers of only few kJ/mol (almost flat surface). Now, given > > these low values of the free energy barriers, I would expect to observe > the > > open-closed transitions in the unbiased simulations. However, we do not > see > > that transition in the unbiased trajectories. > > > > So, my questions are, > > 1) Are the collective variables used here inappropriate? (Although I see > > the open-closed > > transition a many times in the metadynamics trajectory.) > > > > 2) Is the free energy not converged? (plotting hills heights a function > of > > time, decays close to zero after 200-250 ns) > > > > 3) How would I make sure that the free energy is converged? (block > averages > > using -stride in plumed) How would I decide the blocks from the COLVAR > plot? > > > > Any suggestions would be highly appreciated. > > > > -- > > Regards, > > Tarak > > -- > > Gromacs Users mailing list > > > > * Please search the archive at > http://www.gromacs.org/Support/Mailing_Lists/GMX-Users_List before > posting! > > > > * Can't post? Read http://www.gromacs.org/Support/Mailing_Lists > > > > * For (un)subscribe requests visit > > https://maillist.sys.kth.se/mailman/listinfo/gromacs.org_gmx-users or > send a mail to gmx-users-requ...@gromacs.org. > > -- > Gromacs Users mailing list > > * Please search the archive at > http://www.gromacs.org/Support/Mailing_Lists/GMX-Users_List before > posting! > > * Can't post? Read http://www.gromacs.org/Support/Mailing_Lists > > * For (un)subscribe requests visit > https://maillist.sys.kth.se/mailman/listinfo/gromacs.org_gmx-users or > send a mail to gmx-users-requ...@gromacs.org. > -- Regards, Tarak -- Gromacs Users mailing list * Please search the archive at http://www.gromacs.org/Support/Mailing_Lists/GMX-Users_List before posting! * Can't post? Read http://www.gromacs.org/Support/Mailing_Lists * For (un)subscribe requests visit https://maillist.sys.kth.se/mailman/listinfo/gromacs.org_gmx-users or send a mail to gmx-users-requ...@gromacs.org.
Re: [gmx-users] Open-closed transition in a dimeric enzyme, WTM simulations
Dear Tarak, My guess is that your reaction coordinate is ill-chosen and that it fails to capture some significant transitions in orthogonal directions. This can be difficult to know beforehand unfortunately. Kind regards, Erik > On 10 Jun 2016, at 19:09, tarak karmakar wrote: > > Dear All, > I am studying an enzyme where the closing of a loop should happen upon > ligand binding to the active site. In unbiased simulations, even after 300 > ns of simulation time the loop does not close the reaction center. Thus, we > realized that the open-closed conformational change may have a high free > energy barrier, inaccessible by the unbiased trajectory. Thus, we performed > well-tempered metadynamics (WTM) simulations to study that event. > > In WTM simulations, we see the opening and closing of the loop almost five > to six times within 300 ns time span. The free energy associated with this > event has barriers of only few kJ/mol (almost flat surface). Now, given > these low values of the free energy barriers, I would expect to observe the > open-closed transitions in the unbiased simulations. However, we do not see > that transition in the unbiased trajectories. > > So, my questions are, > 1) Are the collective variables used here inappropriate? (Although I see > the open-closed > transition a many times in the metadynamics trajectory.) > > 2) Is the free energy not converged? (plotting hills heights a function of > time, decays close to zero after 200-250 ns) > > 3) How would I make sure that the free energy is converged? (block averages > using -stride in plumed) How would I decide the blocks from the COLVAR plot? > > Any suggestions would be highly appreciated. > > -- > Regards, > Tarak > -- > Gromacs Users mailing list > > * Please search the archive at > http://www.gromacs.org/Support/Mailing_Lists/GMX-Users_List before posting! > > * Can't post? Read http://www.gromacs.org/Support/Mailing_Lists > > * For (un)subscribe requests visit > https://maillist.sys.kth.se/mailman/listinfo/gromacs.org_gmx-users or send a > mail to gmx-users-requ...@gromacs.org. -- Gromacs Users mailing list * Please search the archive at http://www.gromacs.org/Support/Mailing_Lists/GMX-Users_List before posting! * Can't post? Read http://www.gromacs.org/Support/Mailing_Lists * For (un)subscribe requests visit https://maillist.sys.kth.se/mailman/listinfo/gromacs.org_gmx-users or send a mail to gmx-users-requ...@gromacs.org.
[gmx-users] Open-closed transition in a dimeric enzyme, WTM simulations
Dear All, I am studying an enzyme where the closing of a loop should happen upon ligand binding to the active site. In unbiased simulations, even after 300 ns of simulation time the loop does not close the reaction center. Thus, we realized that the open-closed conformational change may have a high free energy barrier, inaccessible by the unbiased trajectory. Thus, we performed well-tempered metadynamics (WTM) simulations to study that event. In WTM simulations, we see the opening and closing of the loop almost five to six times within 300 ns time span. The free energy associated with this event has barriers of only few kJ/mol (almost flat surface). Now, given these low values of the free energy barriers, I would expect to observe the open-closed transitions in the unbiased simulations. However, we do not see that transition in the unbiased trajectories. So, my questions are, 1) Are the collective variables used here inappropriate? (Although I see the open-closed transition a many times in the metadynamics trajectory.) 2) Is the free energy not converged? (plotting hills heights a function of time, decays close to zero after 200-250 ns) 3) How would I make sure that the free energy is converged? (block averages using -stride in plumed) How would I decide the blocks from the COLVAR plot? Any suggestions would be highly appreciated. -- Regards, Tarak -- Gromacs Users mailing list * Please search the archive at http://www.gromacs.org/Support/Mailing_Lists/GMX-Users_List before posting! * Can't post? Read http://www.gromacs.org/Support/Mailing_Lists * For (un)subscribe requests visit https://maillist.sys.kth.se/mailman/listinfo/gromacs.org_gmx-users or send a mail to gmx-users-requ...@gromacs.org.
