AMBER Archive (2007)

Subject: AMBER: Umbrella sampling

From: Franck Vendeix (Franck_Vendeix_at_ncsu.edu)
Date: Fri Feb 09 2007 - 08:37:35 CST

Dear Amber users,

I am a subscriber of the amber reflector mailing list and I sent this
message (see below) to the members of this list 24 hours ago. I believe
that this message did not reach the members since I did not receive it
in my e-mail box. This is my second attempt to try to send it.

------- Original Message --------
Subject: Umbrella Sampling
Date: Thu, 08 Feb 2007 08:45:37 -0500
From: Franck Vendeix <favendei_at_ncsu.edu>
To: amber_at_scripps.edu

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 C1’-C1’ 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 C1’-C1’ distance as the coordinate to
be used to determined the PMF. Although the C1’-C1’ 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 C1’-C1’ 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=’DUMPFREQ’, istep1=10 /

&wt type=’END’ /

DISANG=dist.RST

DUMPAVE=dist_vs_2

Where the dist.RST files contains:

# distance restraint between A C1’ and U C1’

&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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