Dear Amber and Charles
In this case, do I need to run a recharge state also?
Could you please brief a bit more, As I am trying this for the first time I
have confusion about setting up the system that when I am using vdw
interactions does it contains parameters of both states? and for decharge I
need to strip the first state?
I need your suggestions, please.
Thank you
Sadaf
On Mon, Oct 14, 2019 at 3:20 PM Charles Lin <Charles.lin.silicontx.com>
wrote:
> You shouldn't use softcore if your coordinates are being scaled together
> (turn off both your scmasks). Yea the chargemask literally just sets the
> charge of the atoms you indicate to 0, so you could have done it through
> the parameterization or through the crgmask flag, so that's working as
> intended.
>
> On 10/14/19, 6:59 AM, "Sadaf Rani" <sadafrani6.gmail.com> wrote:
>
>
> CAUTION: EXTERNAL EMAIL
>
>
>
> 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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> > > > > AMBER.ambermd.org
> > > > >
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Received on Mon Oct 14 2019 - 08:30:02 PDT
