Dear Charles
thank you for your reply
I am a bit confused here. For system set up do I need to build a second
copy of ligand (BG7) mentioned above which has no charge on it and save the
coordinates of both states (BG6 & BG7) in the same prmtop file?
Could you please elaborate a little more regarding the setting up of system?
Also for vdw state, should I set my system like this?
icfe = 1, clambda = 0.0, scalpha = 0.5, scbeta = 12.0,
logdvdl = 1,
ifmbar = 1, mbar_states= 11,
mbar_lambda= 0.0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0
bar_intervall = 10,
timask1 = ':BG6', timask2 = '',
ifsc = 1, crgmask = ':BG7',
scmask1=':BG6' scmask2='BG7'
crgmask=':BG6'
looking forward to hear from you soon.
Thank you
Sadaf
On Thu, Oct 10, 2019 at 2:13 PM Charles Lin <Charles.lin.silicontx.com>
wrote:
> For decharge step you generally want your endstates to be:
> Lambda 0: Molecule with charge
> Lambda 1.0: Molecule without charge
>
> Therefore you'd want 2 copies of your ligand.
>
> So you'd want
> Timask1=':BG6', timask2=':BG7' (or whatever second copy of your ligand is)
> crgmask=':BG7'
>
> On 10/10/19, 8:16 AM, "Sadaf Rani" <sadafrani6.gmail.com> wrote:
>
>
> CAUTION: EXTERNAL EMAIL
>
>
>
> Dear Amber and Charlie
> I run TI calculation for calculating absolute free energy calculation
> of
> ligand with the following input in decharge step:-
>
> icfe = 1, clambda = 0.0, scalpha = 0.5, scbeta = 12.0,
> logdvdl = 1,
>
> ifmbar = 1, mbar_states= 11,
>
> mbar_lambda= 0.0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0
>
> bar_intervall = 10,
>
> timask1 = ':BG6', timask2 = '',
>
> ifsc = 0, crgmask = ':BG6',
>
> but it gives me following error:-
>
> TI Mask 1 :BG6; matches 27 atoms
> TI Mask 2 matches 0 atoms
> TI region 1: 8591 atoms
> TI region 2: 8564 atoms
> Removing charge of -0.6555 from atom 1
> Removing charge of 0.4043 from atom 2
> Removing charge of 0.1047 from atom 3
> Removing charge of 0.0443 from atom 4
> Removing charge of 0.2450 from atom 5
> Removing charge of -0.7348 from atom 6
> Removing charge of 0.4283 from atom 7
> Removing charge of -0.0045 from atom 8
> Removing charge of 0.2380 from atom 9
> Removing charge of -0.7107 from atom 10
> Removing charge of 0.4056 from atom 11
> Removing charge of 0.0704 from atom 12
> Removing charge of 0.5188 from atom 13
> Removing charge of -0.7055 from atom 14
> Removing charge of 0.4528 from atom 15
> Removing charge of -0.0204 from atom 16
> Removing charge of -0.5253 from atom 17
> Removing charge of 0.2104 from atom 18
> Removing charge of 0.0424 from atom 19
> Removing charge of 0.2913 from atom 20
> Removing charge of -0.0024 from atom 21
> Removing charge of -0.0024 from atom 22
> Removing charge of -0.5859 from atom 23
> Removing charge of 1.3045 from atom 24
> Removing charge of -0.9377 from atom 25
> Removing charge of -0.9377 from atom 26
> Removing charge of -0.9377 from atom 27
> Total charge of -2.00000000 removed from 27 atoms
>
> MBAR - lambda values considered:
> 11 total: 0.0000 0.1000 0.2000 0.3000 0.4000 0.5000 0.6000
> 0.7000
> 0.8000 0.9000 1.0000
> Extra energies will be computed 10000 times.
> Checking for mismatched coordinates.
> ERROR: timask1/2 must match the same number of atoms for
> non-softcore
> run
>
> how should I set input to fix this error
> Looking forward to hearing from you.
> thank you
>
> Sadaf
>
> On Thu, Oct 3, 2019 at 5:13 PM Charles Lin <Charles.lin.silicontx.com>
> wrote:
>
> > You essentially just need to run your production scheme with
> different
> > lambdas by changing the clambda value.
> >
> > 0.0 = your ligand fully exists
> > 1.0 = your ligand has fully disappeared.
> >
> > Follow the folder setup like this:
> > http://ambermd.org/tutorials/advanced/tutorial9/index.html
> >
> > You may want to increase the number of lambda windows you're using
> because
> > your transformation is a lot bigger when you're augmenting both
> > electrostatics and vdws. You may want to considering doing it in
> two steps
> > where you first decharge your molecule then disappear the vdws.
> (Similar
> > to the tutorial except scmask2 and timask2 are both '', and you
> don't run a
> > recharge window.
> >
> > -Charlie
> >
> > On 10/3/19, 11:06 AM, "Sadaf Rani" <sadafrani6.gmail.com> wrote:
> >
> >
> > CAUTION: EXTERNAL EMAIL
> >
> >
> >
> > Dear Amber
> > I am also looking for the same.
> > I have a ligand for my protein for which I want to calculate
> absolute
> > binding energy; in which I want the ligand to disappear
> completely at
> > the
> > start and then appear with all vander waals and electrostatic
> > interactions.
> > As per my understanding(I may be wrong in it), I should set up
> my
> > ligand
> > in solution and complex in solution as per the following input:-
> > Minimization:-
> > &cntrl
> > imin = 1, ntmin = 2,
> > maxcyc = 1000,
> > ntpr = 200, ntwe = 200,
> > ntb = 1,
> > ntr = 1, restraint_wt = 5.00,
> > restraintmask='!:WAT & !.H=',
> >
> > icfe = 1, ifsc = 1, clambda = 0.0, scalpha = 0.5, scbeta =
> 12.0,
> > logdvdl = 0,
> > timask1=':1', scmask1=':1',
> > timask2='', scmask2='',
> > /
> > &ewald
> > /
> >
> > Heating:-
> > &cntrl
> > imin = 0, nstlim = 10000, irest = 0, ntx = 1, dt = 0.002,
> > nmropt = 1,
> > ntt = 1, temp0 = 300.0, tempi = 5.0, tautp = 1.0,
> > ntb = 1,
> > ntc = 2, ntf = 1,
> > ioutfm = 1, iwrap = 1,
> > ntwe = 1000, ntwx = 1000, ntpr = 1000, ntwr = 5000,
> >
> > ntr = 1, restraint_wt = 5.00,
> > restraintmask='!:WAT & !.H=',
> >
> > icfe = 1, ifsc = 1, clambda = 0.5, scalpha = 0.5, scbeta =
> 12.0,
> > logdvdl = 0,
> > timask1=':1', scmask1=':1',
> > timask2='', scmask2='',
> > /
> > &ewald
> > /
> >
> > &wt
> > type='TEMP0',
> > istep1 = 0, istep2 = 8000,
> > value1 = 5.0, value2 = 300.0
> > /
> >
> > &wt type = 'END'
> > /
> >
> > Pressurizing:-
> > &cntrl
> > imin = 0, nstlim = 10000, irest = 1, ntx = 5, dt = 0.002,
> > ntt = 1, temp0 = 300.0, tautp = 1.0,
> > ntp = 1, pres0 = 1.0, taup = 2.0,
> > ntb = 2,
> > ntc = 2, ntf = 1,
> > ioutfm = 1, iwrap = 1,
> > ntwe = 1000, ntwx = 1000, ntpr = 1000, ntwr = 5000,
> >
> > ntr = 1, restraint_wt = 5.00,
> > restraintmask='!:WAT & !.H=',
> >
> > icfe = 1, ifsc = 1, clambda = 0.5, scalpha = 0.5, scbeta =
> 12.0,
> > logdvdl = 0,
> > timask1=':1', scmask1=':1',
> > timask2='', scmask2='',
> > /
> > &ewald
> > /
> > What next? How to set input for absolute free energy
> calculations in
> > order
> > to disappear ligand and slowly appear with increase in lambda?
> >
> > Looking for your kind suggestions, please.
> >
> > Thank you
> >
> >
> > On Wed, Oct 2, 2019 at 4:20 PM Charles Lin <
> Charles.lin.silicontx.com>
> > wrote:
> >
> > > Hi,
> > >
> > > I'd follow mostly the same protocol as a relative binding free
> energy
> > > (where ligand a transforms to ligand b), but instead of having
> a
> > ligand b,
> > > your timask, scmask of those regions becomes nothing
> > > timask2='', scmask2='',
> > >
> > > I would also apply the virtual bond algorithm described here
> to keep
> > your
> > > ligand in the pocket (described as a virtual bond here)
> > > https://pubs.acs.org/doi/pdf/10.1021/jp505777n
> > >
> > > These calculations are fairly expensive to calculate. Relative
> > binding
> > > free energies converge a lot more quickly because the amount of
> > phase space
> > > to sample is already somewhat more limited due to the presence
> of a
> > ligand
> > > you already know its binding pose/pocket position. The less
> data
> > you know
> > > about your system, the less likely you'll place your ligand
> > correctly, and
> > > simple changes such as having a side chain incorrect, could
> vastly
> > give
> > > different absolute binding free energy values.
> > >
> > > -Charlie
> > >
> > > On 10/1/19, 4:26 PM, "Debarati DasGupta" <
> > debarati_dasgupta.hotmail.com>
> > > wrote:
> > >
> > >
> > > CAUTION: EXTERNAL EMAIL
> > >
> > >
> > >
> > > Dear All,
> > >
> > > I have been trying to read more about free energy
> calculations
> > using
> > > TI method implemented in AMBER18. I recently did a webinar by
> CCG
> > group
> > > wherein in MOE2019 they have incorporated the TI
> implementation setup
> > > collaborating with AMBER.
> > >
> > > I did read this publication too from Professor Carlos
> > Simmerling’s
> > > webpage “
> > >
> >
> https://chemrxiv.org/articles/Blinded_Prediction_of_Protein-Ligand_Binding_Affinity_Using_Amber_Thermodynamic_Integration_for_the_2018_D3R_Grand_Challenge_4/8312375/1
> > > ”
> > > This did throw a lot of light on how to exactly setup TI
> > calculations
> > > in AMBER.
> > >
> > > I still have a very fundamental question, it may be very
> stupid,
> > but I
> > > am not sure how to setup TI to calculate the absolute binding
> > affinity of a
> > > ligand towards a protein.
> > > Is there something I am missing totally?
> > > My protein of interest is ABL-kinase and I have a done some
> > co-solvent
> > > simulations to get some hotspots( areas of possible
> ligandibility);
> > I need
> > > to calculate the binding affinity of these small cosolvents
> towards
> > ABL.
> > > TI methods give us a “deldelG”, which is relative binding
> > affinity, if
> > > we have a receptor (say CathepsinS) and have a set of 10+
> ligands
> > with a
> > > common core (scaffold).
> > > If I have one protein +1 ligand and I need to calculate the
> > binding
> > > affinity what is the procedure to be adopted?
> > > Is there a tutorial to do that?
> > >
> > > I am not looking to do MMGBSA/PBSA on this system.
> > >
> > > Thanks
> > >
> > > _______________________________________________
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Received on Thu Oct 10 2019 - 08:00:03 PDT
