Re: [AMBER] Thermodynamic integration

From: Sadaf Rani <sadafrani6.gmail.com>
Date: Mon, 14 Oct 2019 20:02:52 +0100

Dear Charles
Thank you very much for your reply.
As much I understand regarding my system in which I am using linear scaling
scheme for decharge I have to do:-
   icfe = 1
   timask1 = ':BG0', (fully charged)
  timask2 = ':BG1', (no charge)
   ifsc = 0,

and for VDW:-

 icfe = 1
timask1 = ':BG0', (fully charged)
  timask2 = ':BG1', (no charge)
   ifsc = 1,
 scmask1 = ':BG0',
 scmask2 = ':BG1',
crgmask = ':BG0 | BG1',


thanks for your suggestions

Sadaf


On Mon, Oct 14, 2019 at 5:58 PM Charles Lin <Charles.lin.silicontx.com>
wrote:

> In absolute binding free energies, your endpoints are:
> Ligand (fully charge, fully interacting), ligand (no charge full
> interacting), nothing (no charge not interacting)
>
> Decharge does (fully charge, fully interacting) -> (no charge, fully
> interacting)
> VDW does (no charge, fully interacting) -> (no charge, not interacting)
>
> Therefore you don't need a recharge step.
>
> Essentially timask1 and timask2 define your endpoints of your lambda
> windows (0.0 and 1.0).
>
> On 10/14/19, 11:11 AM, "Sadaf Rani" <sadafrani6.gmail.com> wrote:
>
>
> CAUTION: EXTERNAL EMAIL
>
>
>
> 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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> This email message is for the sole use of the intended recipient(s)
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> intended recipient, please contact the sender by reply email and destroy
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> please be advised that the content of this message is subject to access,
> review and disclosure by the sender's Email System Administrator.
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>
> This email message is for the sole use of the intended recipient(s) and
> may contain confidential and privileged information. Any unauthorized
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> intended recipient, please contact the sender by reply email and destroy
> all copies of the original message. If you are the intended recipient,
> please be advised that the content of this message is subject to access,
> review and disclosure by the sender's Email System Administrator.
> _______________________________________________
> AMBER mailing list
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Received on Mon Oct 14 2019 - 12:30:02 PDT
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