AMBER Archive (2007)

Subject: Re: AMBER: Umbrella sampling

From: Franck Vendeix (Franck_Vendeix_at_ncsu.edu)
Date: Wed Feb 14 2007 - 21:13:31 CST

Jerome.GOLEBIOWSKI_at_unice.fr wrote:
> Hi, did you try to read what Richard Lavery made some years ago ?
> maybe it could help.
>
> E. STOFER, C. CHIPOT and R. LAVERY
> Free energy calculations of Watson--Crick base pairing in aqueous
> solution
> J. Am. Chem. Soc. 121, 1999, 9503-9508
>
> In the context of a nucleic acid, base staking is crucial to keep a
> correct angle beteen interacting pairs. Maybe you should consider puting
> a restaint on the dihedral between the NA bases.
> Starting with a bent structure is probably not relevant if you intend to
> draw conclusions for a NA.
> Cheers.
> Jerome
>
>
>
>
>> Dear Amber users,
>>
>> I am trying to determine the delta_G of different types of base pairs by
>> using umbrella sampling with Amber 9.
>> Each system under study consists of a single isolated base pair (e.g.
>> A-U or C-G etc...) surrounded by explicit water molecules (octahedral
>> TIP3PBOX 8.0 A).
>> I designed a protocol to carry out umbrella sampling calculations.
>> Nevertheless I kindly request you to give me your critical point of view
>> on the correctness of this protocol and answer a couple of questions.
>> A-U base pair will be used as an example.
>>
>> On Step1: I minimized the water molecule and the counter ions (Na+) by
>> holding the A-U base pair fixed
>>
>> &cntrl
>>
>> imin = 1,
>>
>> maxcyc = 1000,
>>
>> ncyc = 500,
>>
>> ntb = 1,
>>
>> ntr = 1,
>>
>> cut = 10
>>
>> /
>>
>> Hold the base pair fixed
>>
>> 500.0
>>
>> RES 1 2
>>
>> END
>>
>> END
>>
>> Step2: the entire system (base pair + water + ions) is minimized
>>
>> &cntrl
>>
>> imin = 1,
>>
>> maxcyc = 2500,
>>
>> ncyc = 1000,
>>
>> ntb = 1,
>>
>> ntr = 0,
>>
>> cut = 10
>>
>> /
>>
>> Step3: equilibration of the system from 0 to 300 K for 5ps. This MD is
>> done with weak positional restraints on the base pair during 5ps:
>>
>> &cntrl
>>
>> imin = 0,
>>
>> irest = 0,
>>
>> ntx = 1,
>>
>> ntb = 1,
>>
>> cut = 10,
>>
>> ntr = 1,
>>
>> ntc = 2,
>>
>> ntf = 2,
>>
>> tempi = 0.0,
>>
>> temp0 = 300.0,
>>
>> ntt = 3,
>>
>> gamma_ln = 2.0,
>>
>> nstlim = 5000, dt = 0.001
>>
>> ntpr = 100, ntwx = 100, ntwr = 1000
>>
>> /
>>
>> Keep base pair fixed with weak restraints
>>
>> 10.0
>>
>> RES 1 2
>>
>> END
>>
>> END
>>
>> Step 4: Equilibration at 300 K of the system during 40 ps
>>
>> &cntrl
>>
>> imin = 0, irest = 1, ntx = 7,
>>
>> ntb = 2, pres0 = 1.0, ntp = 1,
>>
>> taup = 2.0,
>>
>> cut = 10, ntr = 0,
>>
>> ntc = 2, ntf = 2,
>>
>> tempi = 300.0, temp0 = 300.0,
>>
>> ntt = 3, gamma_ln = 2.0,
>>
>> nstlim = 40000, dt = 0.001,
>>
>> ntpr = 100, ntwx = 100, ntwr = 1000
>>
>> /
>>
>> The system effectively reached equilibrium at the end of this
>> simulation. However the base pair is not planar anymore and the two
>> aromatic rings formed an angle of ~ 160 deg. Thus the A-U base is
>> slightly bent and as a result the C1ÿ-C1ÿ distance between the base is
>> reduced by ~1 A (angstrom) and measured ~ 9.78 A instead of ~ 10.75 A
>> found in the minimized conformation. This could be explained by the
>> absence of base stacking in the system.
>>
>> My plan is to start the umbrella sampling simulation after the
>> equilibration step 4 and use the C1ÿ-C1ÿ distance as the coordinate to
>> be used to determined the PMF. Although the C1ÿ-C1ÿ is altered after
>> step 4, should the umbrella sampling computation be started from this
>> bent conformation or from the optimized conformation (i.e. start doing
>> umbrella sampling after step 3)?
>>
>> My guess is if I want to skip the equilibrium step 4 I should use
>> implicit water solvent and start the umbrella sampling just after a
>> minimization step. However would it be advisable to work with implicit
>> water solvent in the case of this particular system (A-U base pair)?
>>
>> Is it better to use the distance between the center of mass of each
>> molecule instead of C1ÿ-C1ÿ distance?
>>
>> An example of an MD simulation input file used for the umbrella sampling
>> is showed bellow:
>>
>> &cntrl
>>
>> imin = 0, irest = 1, ntx = 7,
>>
>> ntb = 2, pres0 = 1.0, ntp = 1,
>>
>> taup = 2.0,
>>
>> cut = 10, ntr = 0,
>>
>> ntc = 2, ntf = 2,
>>
>> tempi = 300.0, temp0 = 300.0,
>>
>> ntt = 3, gamma_ln = 2.0,
>>
>> nstlim = 1000, dt = 0.0005,
>>
>> ntpr = 100, ntwx = 100, ntwr = 100
>>
>> /
>>
>> &wt type=ÿDUMPFREQÿ, istep1=10 /
>>
>> &wt type=ÿENDÿ /
>>
>> DISANG=dist.RST
>>
>> DUMPAVE=dist_vs_2
>>
>> Where the dist.RST files contains:
>>
>> # distance restraint between A C1ÿ and U C1ÿ
>>
>> &rst iat=11,44, r1=0., r2=2., r3=2., r4=20., rk2 = 20.,
>>
>> rk3 = 20., /
>>
>> I will use 20 windows with 100 points collected for each (2000 points in
>> total). The time of the simulation is 0.5 ps.
>>
>> Is there any optimal time to be used for umbrella sampling? If yes,
>> where could I find the method to determine this optimization?
>>
>> Which method should be used to choose the best rk2/rk3 values?
>>
>> I thank you in advance for your replies.
>>
>> Regards,
>>
>> Franck
>>
>>
>>
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>>
I thank you Jerome for your reply. I went through the suggested
reference and found some important answers to my questions.
Regards,

Franck
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