Re: Reproducing free energy profile for acetate-guanidinium association

From: Grzegorz Jezierski (jezierski_at_theochem.tu-muenchen.de)
Date: Wed Nov 29 2006 - 06:00:45 CST

Jerome Henin wrote:
> Dear Grzegorz,
>
> On Tuesday 14 November 2006 07:40, Grzegorz Jezierski wrote:
>
>> Dear users,
>>
>> I plan to perform some free energy calculations on systems involving a
>> short DNA fragment complexed/bound to a chromophore molecule. I would
>> like to use ABF method (in NAMD), as an alternative to umbrella
>> sampling. Before, I tried to reproduce the results on
>> acetate-guanidinium association, published in J Chem Phys. (2004),
>> 121(7); p.2904.
>>
>> 1.
>> A 2-ns ABF simulation (Xi= 4.0 --> 12.0 A) yielded strikingly different
>> free energy values than those in the cited paper. I tried to keep as close
>> as possible to the original simulation parameters.
>>
>
> A part of the problem is that although the JCP 2004 paper states that the
> acetate-guanidinium system is restrained to the C2v geometry, the exact
> detail of the restraints is not provided.
> They were:
> {
> angleA1 { angle {A 1 CA} {G 1 N3} {G 1 N1} 40.0 30.0 }
> angleA2 { angle {A 1 CA} {G 1 N3} {G 1 N2} 40.0 30.0 }
> angleB1 { angle {A 1 O1} {A 1 CA} {G 1 N3} 40.0 27.8 }
> angleB2 { angle {A 1 O2} {A 1 CA} {G 1 N3} 40.0 27.8 }
> diheA1 { dihe { A 1 O1 } { A 1 CA } { A 1 O2 } { G 1 N3 } 40.0 0.0 }
> diheA2 { dihe { A 1 O2 } { A 1 CA } { A 1 O1 } { G 1 N3 } 40.0 0.0 }
> diheA3 { dihe { A 1 CA } { G 1 N1 } { G 1 N3 } { G 1 N2 } 40.0 0.0 }
> diheA4 { dihe { A 1 CA } { G 1 N2 } { G 1 N3 } { G 1 N1 } 40.0 0.0 }
> diheB1 { dihe { A 1 CA } { A 1 O1 } { G 1 N1 } { G 1 N3 } 40.0 0.0 }
> diheB2 { dihe { A 1 CA } { A 1 O2 } { G 1 N2 } { G 1 N3 } 40.0 0.0 }
> }
>
> As you can see, this set of restraints is more complete and tighter that what
> you used. This most probably accounts for the difference in the resulting
> PMFs.
>
>
>
>> Apart from Langevin
>> dynamics (LD), a 2-ns 'normal' (i.e. without Langevin algorithm) MD run was
>> also performed. What I got was a nice looking but very shallow profile in
>> the case of 'normal' MD, and somewhat an anomalous profile from LD.
>>
>
> If by 'normal' MD you mean that you did not apply any thermostat, then it is
> not a good idea. ABF is really meant for constant temperature simulations.
>
> The problems you mention below are probably connected to insufficient
> convergence. For this system, in all cases but the tightly restrained dimer
> we used, long simulations (many ns) will be required to reach some kind of
> convergence. We commented on that in the 2004 paper.
>
> Best regards,
> Jerome
>
>
>
>> 2.
>> Switching a part of harmonic restraints off didn't affect the depth of the
>> minima; only the asymptotic value (for large Xi) would now tend to zero.
>>
>> 3.
>> Four 0.5-ns simulations (Xi= 4.0-->6.0; 6.0-->8.0; 8.0-->10.0; 10.0-->12.0)
>> produced a discontinuous deltaG dependence which tends to zero for
>> Xi=12.0A.
>>
>> From this data, estimated deltaG of dimer dissociation is about +3
>> kcal/mol.
>>
>> 4.
>> The important point is that I wasn't able to make the program decrease
>> the value of Xi. In this case, only zero deltaG values were printed to
>> the output file. I could only obtain non-zero result when increasing the
>> value of Xi (e.g. from 4.0 to 12.0 A), therefore simulating dissociation
>> rather than association of the complex.
>>
>> Comments are welcome. Below: the ABF section of the input file.
>> Regards,
>> Grzegorz Jezierski
>>
>>
>>
>> =======================================
>> abf coordinate distance-com
>> abf abf1 { 11 12 16 17 }
>> abf abf2 { 1 2 5 8 }
>> abf xiMin 4.0
>> abf xiMax 12.0
>> abf dxi 0.1
>> abf fullSamples 500
>> abf outfile ace_guanid_dGfinal.01.dat
>> abf outputFreq 100
>> abf historyFile abf_forces.01.dat
>> abf inFiles { }
>> abf distFile abf_distrib.01.dat
>> abf WriteXiFreq 100
>> abf ForceConst 10.0
>> abf dSmooth 0.4
>>
>> abf RestraintList {
>> CNN_COO_plane1 { dihe {GUAN 2 H21} {GUAN 2 N2} {ACET 1 C2} {ACET 1 O1} 5.0
>> 0.0 } CNN_COO_plane2 { dihe {GUAN 2 H22} {GUAN 2 N2} {ACET 1 C2} {ACET 1
>> O2} 5.0 0.0 } }
>>
>
>

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