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From: David A. Case <case_at_scripps.edu>

Date: Tue 24 Sep 2002 07:14:01 -0700

On Tue, Sep 24, 2002, hagop demirdjian wrote:

*>
*

*>
*

*> What is the expression of V(lambda) in GIBBS (I could not find it in the
*

*> manual, so I assumed it is linear : V(l) = l*V1 + (1-l)*V0
*

The mixing depends on the value of IOLEPS (see p. 173 of the manual); I

agree that the documentation could be more specific here. Also, if you

are doing thermodynamic integration in gibbs, the mixing is always linear,

as you write above.

Note also that, in sander, lambda=0 is the "regular" state in LEaP, and

lambda=1 is the perturbed state. The reverse convention is used in gibbs

(see. p. 158, section 7.1).

*>
*

*> I simulated a mutation where atoms disapear. I computed DeltaGs in GIBBS and
*

*> SANDER : in GIBBS, dV/dl values are all negative and decrease from -16 to
*

*> -30 kCal/mol/l in SANDER, I used klambda = 4, and got values decreasing
*

*> quickly from 350 to -20 and increasing to 0 at lambda =1.
*

*>
*

*> Both integrations give the same DeltaGs. I assume that differences are
*

*> due to a difference in the expressions of the V(l). Am I right ?
*

This should be the case, although (see below) one would really need to know

more about how you did the gibbs calculations to say more. I'd be very

interested in seeing your results (and input files) if you feel comfortable

with that. We'd like to generate a tutorial that compares making atoms

disappear in sander vs. gibbs, to understand better what the potential

advantages and pitfalls are in each approach.

*>
*

*> And finally, what in your opinion is best suited for TI with vanishing
*

*> atoms ? : SANDER with klambda = 4 or GIBBS with an appropriate value ISDX0 ?
*

*>
*

This is quite a complex question. Certainly, gibbs has been the "default" way

in Amber for some time, but you need to be careful about setting a number of

parameters, in addition to ISDX0. Care needs to be taken in gibbs about

handling perturbations that change bond lengths. In April, Dave Pearlman

posted the following:

In general, for ANY Gibbs free energy simulation you should turn on SHAKE for

all bonds, set NCORC=1 and set INTPRT = 5. These should be the defaults for

a free energy simulation.

Sander is much simpler, which has both good a bad points. With klambda=4, the

variation in <dV/dl> from one lambda value to another can be pretty steep,

esp. for small lambda. This may make the integral difficult to evaluate, and

we are still working on deciding the best way to handle this. Furthermore,

since the internal contributions are not removed, you have to be sure to

subtract two comparable sides of a thermodynamic cycle (e.g. make the atoms

disappear in both gas and solution, and take the difference.) On the plus

side, TI in sander runs in parallel, uses the latest advances in PME

methodology, and can be run with the latest force fields. But if the ISDX0

"trick" used in gibbs (or something similar) is really the best, then it

should be moved into sander as well; what the best course to take here is

still a matter of discussion among the developers.

Disclaimer: most of the free energy calculations I do are simpler, "charging"

calculations, where one is just changing from a deprotonated to a protonated

form of a side chain (or similar). In a sense, this is what sander was

designed to be "good" at, but it should also give correct results for a much

wider range of perturbations. Comments from people with more experience here

would be very welcome.

..good luck....dac

Date: Tue 24 Sep 2002 07:14:01 -0700

On Tue, Sep 24, 2002, hagop demirdjian wrote:

The mixing depends on the value of IOLEPS (see p. 173 of the manual); I

agree that the documentation could be more specific here. Also, if you

are doing thermodynamic integration in gibbs, the mixing is always linear,

as you write above.

Note also that, in sander, lambda=0 is the "regular" state in LEaP, and

lambda=1 is the perturbed state. The reverse convention is used in gibbs

(see. p. 158, section 7.1).

This should be the case, although (see below) one would really need to know

more about how you did the gibbs calculations to say more. I'd be very

interested in seeing your results (and input files) if you feel comfortable

with that. We'd like to generate a tutorial that compares making atoms

disappear in sander vs. gibbs, to understand better what the potential

advantages and pitfalls are in each approach.

This is quite a complex question. Certainly, gibbs has been the "default" way

in Amber for some time, but you need to be careful about setting a number of

parameters, in addition to ISDX0. Care needs to be taken in gibbs about

handling perturbations that change bond lengths. In April, Dave Pearlman

posted the following:

In general, for ANY Gibbs free energy simulation you should turn on SHAKE for

all bonds, set NCORC=1 and set INTPRT = 5. These should be the defaults for

a free energy simulation.

Sander is much simpler, which has both good a bad points. With klambda=4, the

variation in <dV/dl> from one lambda value to another can be pretty steep,

esp. for small lambda. This may make the integral difficult to evaluate, and

we are still working on deciding the best way to handle this. Furthermore,

since the internal contributions are not removed, you have to be sure to

subtract two comparable sides of a thermodynamic cycle (e.g. make the atoms

disappear in both gas and solution, and take the difference.) On the plus

side, TI in sander runs in parallel, uses the latest advances in PME

methodology, and can be run with the latest force fields. But if the ISDX0

"trick" used in gibbs (or something similar) is really the best, then it

should be moved into sander as well; what the best course to take here is

still a matter of discussion among the developers.

Disclaimer: most of the free energy calculations I do are simpler, "charging"

calculations, where one is just changing from a deprotonated to a protonated

form of a side chain (or similar). In a sense, this is what sander was

designed to be "good" at, but it should also give correct results for a much

wider range of perturbations. Comments from people with more experience here

would be very welcome.

..good luck....dac

-- ================================================================== David A. Case | e-mail: case_at_scripps.edu Dept. of Molecular Biology, TPC15 | fax: +1-858-784-8896 The Scripps Research Institute | phone: +1-858-784-9768 10550 N. Torrey Pines Rd. | home page: La Jolla CA 92037 USA | http://www.scripps.edu/case ==================================================================Received on Tue Sep 24 2002 - 07:14:01 PDT

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