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From: Brian Radak <radak004.umn.edu>

Date: Tue, 7 Aug 2012 10:09:53 -0400

Henry,

I'm not an expert on ligand binding, but I believe the cycle in the

tutorial will be compatible with QM/MM. The complication would be that

there are different heats of formation for the ligands if they differ in

the number and kinds of atoms. This will appear as a (probably unknown)

constant shift in the *relative* free energy of transformation between

ligands because the potential energies are on different scales.

However, if you calculate two relative free energies (one in solution and

one in the protein), then the shift will be the same in both legs and

formally cancel out when you calculate a relative binding free energy. You

can do the math yourself by assuming a constant in each QM Hamiltonian that

is only a function of the kinds of QM atoms and not their coordinates. The

constants will come out of the configuration integrals and thus be additive

to the free energy.

As for changing tempi, that may in fact be advantageous, but will not

change the fact that energy is not conserved. That behavior should only be

desired/expected when ntt=0. Of course you will probably not get physically

meaningful results unless the system is first equilibrated near the

temperature of interest (look up ensemble equivalence in the book by Allen

and Tildesley for example).

Regards,

Brian

On Mon, Aug 6, 2012 at 6:51 PM, Pin-Chih Su (Henry Su) <psu4.uic.edu> wrote:

*> Hi Brian,
*

*>
*

*> Thanks for the response. I am trying tempi = 100 & 150 and will let you
*

*> know the result.
*

*>
*

*> Could you explain in more details about "how to carefully calculated or
*

*> canceled out byan appropriate thermodynamic cycle" to overcome the subtle
*

*> QMMM TI difficulties? If I follow and modify the protocol of amber TI
*

*> tutorial, <http://ambermd.org/tutorials/advanced/tutorial9/> will I
*

*> overcome the subtle QMMM TI difficulty? Or there are something important
*

*> tips not mentioned in the tutorial?
*

*>
*

*> When visualized the QMMM TI trajectory, I don't see weird points. The
*

*> ligand still binds to the protein active site with normal fluctuation; no
*

*> blow up. The following is the RMSD v.s. time plot of the 100 ps
*

*> production run in step 3, V0 group.
*

*>
*

*> http://i1076.photobucket.com/albums/w454/happypsu4/RMSD.jpg
*

*>
*

*> Here is my RMSD script
*

*>
*

*> ######################################
*

*> cat << EOF > AAA.calc_rms
*

*>
*

*> trajin BBB.mdcrd
*

*>
*

*> reference C.inpcrd
*

*>
*

*> rms reference mass out AAA.rms .N,CA,C time 0.5
*

*>
*

*> EOF
*

*>
*

*> $AMBERHOME/bin/ptraj C.prmtop < AAA.calc_rms
*

*> ###############################################
*

*>
*

*> Please let me know if any comment.
*

*>
*

*> Many thanks,
*

*> Henry
*

*>
*

*> On Fri, Aug 3, 2012 at 1:44 PM, Brian Radak <radak004.umn.edu> wrote:
*

*>
*

*> > Hi Henry,
*

*> >
*

*> > You appear to be running thermostatted MD (ntt != 1 and gamma_ln > 0), in
*

*> > which case energy shouldn't be conserved, especially when you set tempi =
*

*> > 0., as the system quickly converts potential energy into kinetic energy.
*

*> > You might consider speeding that up by setting tempi > 0 or using various
*

*> > heating protocols.
*

*> >
*

*> > As for QM/MM, I believe it is quite normal for the energy to jump as the
*

*> QM
*

*> > code includes atomic heats of formation and therefore has a different
*

*> zero
*

*> > of potential energy. This is a subtle difficulty in performing TI with
*

*> > QM/MM because the zero of energy will be an offset in any free energies
*

*> > that you compute and must either be carefully calculated or canceled out
*

*> by
*

*> > an appropriate thermodynamic cycle.
*

*> >
*

*> > Are your dynamics unstable? Relatively large changes in energy during
*

*> > equilibration are not necessarily cause for concern unless you are
*

*> getting
*

*> > vlimit or SHAKE errors.
*

*> >
*

*> > Regards,
*

*> > Brian
*

*> >
*

*> > On Fri, Aug 3, 2012 at 1:44 PM, Pin-Chih Su (Henry Su) <psu4.uic.edu>
*

*> > wrote:
*

*> >
*

*> > > Dear Amber,
*

*> > >
*

*> > > When I run a TI job, the energy doesn't seem to conserve in each
*

*> > clambda
*

*> > > step in no matter step 1, step 2 (soft core potential step) and step 3.
*

*> > > The total energy always drops significantly at the beginning of each
*

*> > stage
*

*> > > (minimization, constant volume equilibrium, constant
*

*> > > pressure equilibrium and production run). Moreover, when MD enters
*

*> into a
*

*> > > QMMM production run, the total energy will drop again and then reach a
*

*> > > higher value than the total energy of minimization and equilibrium.
*

*> > Please
*

*> > > see the following Xmgrace figures for more details.
*

*> > >
*

*> > > *TI_energy<
*

*> > > http://i1076.photobucket.com/albums/w454/happypsu4/TI_energy.png>
*

*> > > (**
*

*> http://i1076.photobucket.com/albums/w454/happypsu4/TI_energy.png**)*
*

*> > > *TI_pressure<
*

*> > > http://i1076.photobucket.com/albums/w454/happypsu4/TI_pressure.png>(
*

*> > > http://i1076.photobucket.com/albums/w454/happypsu4/TI_pressure.png)*
*

*> > > *TI_temperature<
*

*> > > http://i1076.photobucket.com/albums/w454/happypsu4/TI_temperature.png
*

*> >(
*

*> > >
*

*> http://i1076.photobucket.com/albums/w454/happypsu4/TI_temperature.png)*
*

*> > >
*

*> > >
*

*> > > The following is my Amber TI script in step 1 (to simplify, I just
*

*> show
*

*> > > half of the script, as in a group ):
*

*> > >
*

*> > > mask0=':MAA.F14,CL17'
*

*> > > mask1=
*

*> > >
*

*> > > for X in 1,2,3
*

*> > >
*

*> > > do
*

*> > >
*

*> > > ###################### minimization step
*

*> ################################
*

*> > >
*

*> > > imin = 1,
*

*> > > maxcyc = 2000,
*

*> > > ntmin = 2,
*

*> > > ntpr = 100,
*

*> > > ntf = 2,
*

*> > > ntc = 1, (I also tried ntc=2 here)
*

*> > > ntb = 1,
*

*> > > cut = 10.0,
*

*> > > icfe = 1,
*

*> > > clambda = 0.${X},
*

*> > > ifsc=0,
*

*> > > crgmask='${mask0}',
*

*> > > &end
*

*> > > ###########################Constant volume equilibrium to equilibrate
*

*> > > temperature ######################################
*

*> > >
*

*> > > imin = 0,
*

*> > > irest = 0,
*

*> > > ntx = 1,
*

*> > > ntb = 1,
*

*> > > cut = 10.0,
*

*> > > ntr = 1,
*

*> > > ntc = 2,
*

*> > > ntf = 2,
*

*> > > tempi = 0.0,
*

*> > > temp0 = 300.0,
*

*> > > ntt = 3,
*

*> > > gamma_ln = 2.0,
*

*> > > nstlim = 50000,
*

*> > > dt = 0.001,
*

*> > > ntpr = 250,
*

*> > > ntwx = 250,
*

*> > > ntwr = 2500,
*

*> > > icfe = 1,
*

*> > > clambda = 0.${X},
*

*> > > ifsc=0,
*

*> > > crgmask='${mask0}',
*

*> > > /
*

*> > > Keep the Protein fixed with weak restraints
*

*> > > 10.0
*

*> > > RES 1 258
*

*> > > /
*

*> > >
*

*> > > END
*

*> > >
*

*> > > ##################################### Constant Pressure equilibrium to
*

*> > get
*

*> > > a proper density #########################
*

*> > > imin = 0,
*

*> > > irest = 1,
*

*> > > ntx = 7,
*

*> > > ntb = 2,
*

*> > > pres0 = 1.0,
*

*> > > ntp = 1,
*

*> > > taup = 2.0,
*

*> > > cut = 10,
*

*> > > ntr = 0,
*

*> > > ntc = 2,
*

*> > > ntf = 2,
*

*> > > tempi = 300.0,
*

*> > > temp0 = 300.0,
*

*> > > ntt = 3,
*

*> > > gamma_ln = 2.0,
*

*> > > nstlim = 50000,
*

*> > > dt = 0.001
*

*> > > ntpr = 250,
*

*> > > ntwx = 250,
*

*> > > ntwr = 2500,
*

*> > > icfe = 1,
*

*> > > clambda = 0.${X},
*

*> > > ifsc=0,
*

*> > > crgmask='${mask0}',
*

*> > > &end
*

*> > > ############################QMMM production
*

*> > > run###############################################
*

*> > > imin = 0,
*

*> > > ntx = 5,
*

*> > > irest = 1,
*

*> > > ntb = 2,
*

*> > > ntp = 1,
*

*> > > pres0 = 1.0,
*

*> > > taup = 2.0,
*

*> > > ntf = 1,
*

*> > > ntc = 1,
*

*> > > cut = 10.0,
*

*> > > temp0 = 300.0,
*

*> > > ntt = 3,
*

*> > > gamma_ln = 2.0,
*

*> > > nstlim = 50000,
*

*> > > dt = 0.001,
*

*> > > ntpr = 250,
*

*> > > ntwr = 2500,
*

*> > > ntwx = 250,
*

*> > > icfe=1,
*

*> > > clambda = 0.${X},
*

*> > > ifsc=0,
*

*> > > crgmask='${mask0}',
*

*> > > ifqnt = 1
*

*> > > /
*

*> > > &qmmm
*

*> > > iqmatoms= 3868,3869,3870,3871,3872,
*

*> > > 3873,3874,3875,3876,3877,
*

*> > > 3878,3879,3880,3881,3882,
*

*> > > 3883,3884,3885,3886,3887,
*

*> > > 3888,3889,3890,1395,1394,
*

*> > > 1396,1398,1399,2328,2327,
*

*> > > 3833,3834,3835,3836,3837,
*

*> > > 3838,3839,3840,3841,3862,
*

*> > > 3863,3864,3865,3866,3867,
*

*> > > qmchage=-1,
*

*> > > qm_theory='PM3',
*

*> > > qmshake=0,
*

*> > > qm_ewald=1,
*

*> > > qm_pme=1,
*

*> > > /
*

*> > > &end
*

*> > >
*

*> > >
*

*> > >
*

*> >
*

*> ############################################################################
*

*> > >
*

*> > > I have tried
*

*> > >
*

*> > > a. turn off QMMM. Or keep QMMM but with qmshake=1,. The same issue
*

*> > > b. Run in both Amber 11 & 12, The same issue
*

*> > > c. Turn on / off SHAKE. The same issue.
*

*> > > d. Turn off Langevin Dynamic. The same issue
*

*> > > e. Switch to Andersen temperature control. The same issue.
*

*> > > f. Prepare new .prmtop and .inpcrd files and run again. The same issue
*

*> > > g. I have set ntpr=1 and check all the .out files by "gvim -d" and
*

*> total
*

*> > > energies, temperature, pressure and all the MM components are the same
*

*> in
*

*> > > the same group file.
*

*> > > h. The restart files from V0 to V1 are identical.
*

*> > >
*

*> > > I only tried 9 windows so far.
*

*> > > clambda = 0.${X}, for X in 1 2 3 4 5 6 7 8 9
*

*> > > But I guess number of windows is not the issue here.
*

*> > >
*

*> > > Please let me know if any comment. Many comments.
*

*> > >
*

*> > > Henry
*

*> > > _______________________________________________
*

*> > > AMBER mailing list
*

*> > > AMBER.ambermd.org
*

*> > > http://lists.ambermd.org/mailman/listinfo/amber
*

*> > >
*

*> >
*

*> >
*

*> >
*

*> > --
*

*> > ================================ Current Address =======================
*

*> > Brian Radak : BioMaPS
*

*> > Institute for Quantitative Biology
*

*> > PhD candidate - York Research Group : Rutgers, The State
*

*> > University of New Jersey
*

*> > University of Minnesota - Twin Cities : Center for
*

*> Integrative
*

*> > Proteomics Room 308
*

*> > Graduate Program in Chemical Physics : 174 Frelinghuysen Road,
*

*> > Department of Chemistry : Piscataway, NJ
*

*> > 08854-8066
*

*> > radak004.umn.edu :
*

*> > radakb.biomaps.rutgers.edu
*

*> > ====================================================================
*

*> > Sorry for the multiple e-mail addresses, just use the institute
*

*> appropriate
*

*> > address.
*

*> > _______________________________________________
*

*> > AMBER mailing list
*

*> > AMBER.ambermd.org
*

*> > http://lists.ambermd.org/mailman/listinfo/amber
*

*> >
*

*>
*

*>
*

*>
*

*> --
*

*>
*

*> Pin-Chih Su (Henry Su)
*

*>
*

*> Graduate Student
*

*>
*

*> Center for Pharmaceutical Biotechnology (MC 870)
*

*>
*

*> College of Pharmacy, University of Illinois at Chicago
*

*>
*

*> 900 South Ashland Avenue, Room 1052
*

*>
*

*> Chicago, IL 60607-7173
*

*>
*

*> office 312-996-5388
*

*>
*

*> fax 312-413-9303
*

*> _______________________________________________
*

*> AMBER mailing list
*

*> AMBER.ambermd.org
*

*> http://lists.ambermd.org/mailman/listinfo/amber
*

*>
*

Date: Tue, 7 Aug 2012 10:09:53 -0400

Henry,

I'm not an expert on ligand binding, but I believe the cycle in the

tutorial will be compatible with QM/MM. The complication would be that

there are different heats of formation for the ligands if they differ in

the number and kinds of atoms. This will appear as a (probably unknown)

constant shift in the *relative* free energy of transformation between

ligands because the potential energies are on different scales.

However, if you calculate two relative free energies (one in solution and

one in the protein), then the shift will be the same in both legs and

formally cancel out when you calculate a relative binding free energy. You

can do the math yourself by assuming a constant in each QM Hamiltonian that

is only a function of the kinds of QM atoms and not their coordinates. The

constants will come out of the configuration integrals and thus be additive

to the free energy.

As for changing tempi, that may in fact be advantageous, but will not

change the fact that energy is not conserved. That behavior should only be

desired/expected when ntt=0. Of course you will probably not get physically

meaningful results unless the system is first equilibrated near the

temperature of interest (look up ensemble equivalence in the book by Allen

and Tildesley for example).

Regards,

Brian

On Mon, Aug 6, 2012 at 6:51 PM, Pin-Chih Su (Henry Su) <psu4.uic.edu> wrote:

-- ================================ Current Address ======================= Brian Radak : BioMaPS Institute for Quantitative Biology PhD candidate - York Research Group : Rutgers, The State University of New Jersey University of Minnesota - Twin Cities : Center for Integrative Proteomics Room 308 Graduate Program in Chemical Physics : 174 Frelinghuysen Road, Department of Chemistry : Piscataway, NJ 08854-8066 radak004.umn.edu : radakb.biomaps.rutgers.edu ==================================================================== Sorry for the multiple e-mail addresses, just use the institute appropriate address. _______________________________________________ AMBER mailing list AMBER.ambermd.org http://lists.ambermd.org/mailman/listinfo/amberReceived on Tue Aug 07 2012 - 07:30:02 PDT

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