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From: <Jerome.GOLEBIOWSKI.unice.fr>

Date: Mon, 12 Feb 2007 10:33:18 +0100

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
*

*>
*

*>
*

*>
*

*> -----------------------------------------------------------------------
*

*> The AMBER Mail Reflector
*

*> To post, send mail to amber.scripps.edu
*

*> To unsubscribe, send "unsubscribe amber" to majordomo.scripps.edu
*

Date: Mon, 12 Feb 2007 10:33:18 +0100

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

-- 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 ----------------------------------------------------------------------- The AMBER Mail Reflector To post, send mail to amber.scripps.edu To unsubscribe, send "unsubscribe amber" to majordomo.scripps.eduReceived on Sun Feb 18 2007 - 06:07:11 PST

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