Dear Charles
I set my system in which BG0 library contains charges however there is no
charge for BG1 state and I combined the two with same coordinates and
parameters in the same file after that I run a short minimization with
inputs as below:-
minimization
&cntrl
imin = 1, ntmin = 2,
maxcyc = 100,
ntpr = 20, ntwe = 20,
ntb = 1,
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 = ':BG0', timask2 = ':BG1',
scmask1 = ':BG0', scmask2 = ':BG1'
crgmask=':BG1'
/
&ewald
/
It gives me following in output calculation:-
5. REFERENCE ATOM COORDINATES
default_name
Mask !:WAT & !.H=; matches 32 atoms
TI Mask 1 :BG0; matches 27 atoms
TI Mask 2 :BG1; matches 27 atoms
TI region 1: 8682 atoms
TI region 2: 8682 atoms
SC Mask 1 :BG0; matches 27 atoms
SC Mask 2 :BG1; matches 27 atoms
Removing charge of 0.0000 from atom 28
Removing charge of 0.0000 from atom 29
Removing charge of 0.0000 from atom 30
Removing charge of 0.0000 from atom 31
Removing charge of 0.0000 from atom 32
Removing charge of 0.0000 from atom 33
Removing charge of 0.0000 from atom 34
Removing charge of 0.0000 from atom 35
Removing charge of 0.0000 from atom 36
Removing charge of 0.0000 from atom 37
Removing charge of 0.0000 from atom 38
Removing charge of 0.0000 from atom 39
Removing charge of 0.0000 from atom 40
Removing charge of 0.0000 from atom 41
Removing charge of 0.0000 from atom 42
Removing charge of 0.0000 from atom 43
Removing charge of 0.0000 from atom 44
Removing charge of 0.0000 from atom 45
Removing charge of 0.0000 from atom 46
Removing charge of 0.0000 from atom 47
Removing charge of 0.0000 from atom 48
Removing charge of 0.0000 from atom 49
Removing charge of 0.0000 from atom 50
Removing charge of 0.0000 from atom 51
Removing charge of 0.0000 from atom 52
Removing charge of 0.0000 from atom 53
Removing charge of 0.0000 from atom 54
Total charge of 0.00000000 removed from 27 atoms
Am I doing right? crgmask=':BG1' indicates that charges are already
removed from the BG1 state then why I am getting this charge removal data
is regarding BG1?
I have attached the output file for reference.
I need your guideline, please.
thank you in advance.
Sadaf
On Thu, Oct 10, 2019 at 7:51 PM Charles Lin <Charles.lin.silicontx.com>
wrote:
> Yea you basically want an identical copy of the ligand (same parameters,
> same coordinates). You can use the combine call in tleap to create a
> topology this way (similar to how you use the combine call in a relative
> binding free energy calculation.
>
> On 10/10/19, 10:45 AM, "Sadaf Rani" <sadafrani6.gmail.com> wrote:
>
>
> CAUTION: EXTERNAL EMAIL
>
>
>
> 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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