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 03 2019 - 08:30:02 PDT
