AMBER Archive (2007)

Subject: Re: AMBER: Umbrella sampling

From: Jerome.GOLEBIOWSKI_at_unice.fr
Date: Mon Feb 12 2007 - 03:33:18 CST

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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-- 
Jerome Golebiowski, PhD
Lab. Chemistry of Bioactive Molecules and Aromas, 
Team Chemometrics and Molecular Modeling
University of Nice, parc Valrose
06108 Nice Cedex2 France
tel : +33 (0)4 92 07 61 03
http://www.unice.fr/lcmba
http://www.unice.fr/lcmba/golebiowski
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