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From: Brunsteiner, Michael <micb@ui...>  20070216 01:50:23

Dear all, I just tried use the new nonpolar feature with apbs, and encountered some difficulties there. 1) For a start I used the input files from the apbs0.5.0/examples/alkanes/ directory, and a medium size organic molecule with the Amber (actually GAFF) LJ parmeters and AM1BCC charges. I find that:  I get exactly the same apolEnergy no matter what values I choose for dime and/or glen.  the result DOES vary if I change any of gamma, sdens, or press is this supposed to be like that ?? 2) results are VERY sensitive to the the parameter press ... what is this actually ? the documentation says this is "the solvent pressure in Å3" or in kJ mol1 Å3 ... which of the two is unclear, and the value used in the example files (0.2394) does not seem to correspond to ambient pressure (in neither of the two units) ?? 3) I'd like to calculate binding energies (proteinligand) has anybody tried out yet how these new nonpolar energies perform when combined with electrostatic (PB) energies ?? and do I have to expect the optimal parameters (gamma, srad) to be different then ?? 4) are the parameters used in the input file in the examples folder those optimized parameters that were published in Wagoner and Baker, 2006 ? Thanks in advance for any help!! regards, Michael 
From: Nathan Baker <baker@cc...>  20070217 18:50:54

Hello  > 1) For a start I used the input files from the > apbs0.5.0/examples/alkanes/ directory, and a medium > size organic molecule with the Amber (actually GAFF) > LJ parmeters and AM1BCC charges. I find that: >  I get exactly the same apolEnergy no matter > what values I choose for dime and/or glen. Oops  there appears to be a disconnect between the code and the =20 documentation. At this point, hardcoded parameters for the =20 integration are used (see Vacc_wcaEnergyAtom in src/generic/vacc.c); =20 dime/glen are ignored. Sorry about that. >  the result DOES vary if I change any of > gamma, sdens, or press > is this supposed to be like that ?? As the documentation describes (see http://apbs.sourceforge.net/doc/=20 userguide/index.html#apolar and, in particular, http://=20 apbs.sourceforge.net/doc/userguide/images/nonpolarenergy.png), =20 these are the coefficients which weight the various terms of the =20 energy function so the energy definitely should change with these =20 parameters. > 2) results are VERY sensitive to the the parameter > press ... what is this actually ? > the documentation says this is "the solvent pressure in =C53" > or in kJ mol1 =C53 ... which of the two is unclear, It's kJ mol^{1} A^{3}; sorry about that. > and the > value used in the example files (0.2394) does not seem > to correspond to ambient pressure (in neither of the two units) ?? No  and it should not correspond to ambient pressure. This =20 describes the solvent pressure for apolar cavity terms. These =20 parameters more comparable to a hard sphere fluid pressure  the =20 actual pressure in the solvent is dramatically affected by attractive =20= terms as well. > 3) I'd like to calculate binding energies (proteinligand) > has anybody tried out yet how these new nonpolar energies > perform when combined with electrostatic (PB) energies ?? > and do I have to expect the optimal parameters (gamma, srad) > to be different then ?? We've found the optimal parameters to work well in other force =20 calculations as well. However, the values change a bit when we try =20 to apply them to alkanes. I'm not sure how this well affect ligand =20 binding; this is something we're looking at as well. > 4) are the parameters used in the input file in > the examples folder those optimized parameters that > were published in Wagoner and Baker, 2006 ? Yes, but these correspond to the parameters in the *erratum* for that =20= paper. Thanks for your comments; we'll make sure to address all these issues =20= by the next release.  Nathan > Thanks in advance for any help!! > > regards, > Michael > > > > =20= >  > Take Surveys. Earn Cash. Influence the Future of IT > Join SourceForge.net's Techsay panel and you'll get the chance to =20 > share your > opinions on IT & business topics through brief surveysand earn cash > http://www.techsay.com/default.php?=20 > page=3Djoin.php&p=3Dsourceforge&CID=3DDEVDEV > _______________________________________________ > apbsusers mailing list > apbsusers@... > https://lists.sourceforge.net/lists/listinfo/apbsusers  Associate Professor, Dept. of Biochemistry and Molecular Biophysics Center for Computational Biology, Washington University in St. Louis Web: http://cholla.wustl.edu/ 
From: Brunsteiner, Michael <micb@ui...>  20070218 00:04:59

Nathan, Thanks for your elaborate reply to my questions, They are very helpful! I have a couple more questions, I am afraid, and I'd be very grateful for any comments of yours, provided there are any straight forward answers at all. > No  and it should not correspond to ambient pressure. This > describes the solvent pressure for apolar cavity terms. I assume that the value you use (0.2394) is a consequence of the algorithm and not optimized for any particular kind of system, or is it ? > We've found the optimal parameters to work well in other force > calculations as well. I am primarily interested in energies, rather than forces, The latter being derivaties of the energies, means that, if you optimize your model to obtain correct forces, the resulting energies might still be off by some constant value. Can I expect the nonpolar energies resulting from your algorithms to be consistent with the electrostatic energies I get from PB calculations (provided of course the PB parameters, radii, charges, epsilon_P are appropriate) Talking about PB parameters, I've done some work comparing binding energies from PB calculations combined with simple DeltaSASA based nonpolar energies, Notwithstanding the known shortcomings of the latter model, did you find any particular set of PB parameters  e.g. Bondi vs Parse vs some, possibly scaled, force field based radii, or AM1BCC vs force field based charges, etc  to perform better than others ? In my, but small, test set CHARMm based radii plus CHARMm (mind the lower case m) peptide charges combined with ESP charges for ligand and epsilon_P=1 seemed to perform best, closely followed by the parameters suggested by Nina and Roux, 1997. However, both these two, and a number of other parameter sets/combinations I tried did NOT provide really satisfactory results in terms of reproducing experimental binding affinities. Again, this might be due to the poor model for the nonpolar terms. Considering this it is, of course, very important to improve such nonpolar models, as you did in your recent publication  and I wonder if, from this work, you gained any insights into not only nonpolar forces, but also in the appropriate parameterization of PB models ? thanks again & best wishes! Michael 
From: Nathan Baker <baker@cc...>  20070220 13:57:34

Hi Michael  > I assume that the value you use (0.2394) is a consequence of > the algorithm and not optimized for any particular kind > of system, or is it ? It's been optimized using nonpolar solvation forces for protein structures but found to give accurate nonpolar solvation forces for RNA as well. >> We've found the optimal parameters to work well in other force >> calculations as well. > > I am primarily interested in energies, rather than forces, > The latter being derivaties of the energies, means that, if you > optimize your model to obtain correct forces, the resulting > energies might still be off by some constant value. Right. We're working on applying the approaches outlined in Swanson JMJ, Wagoner JA, Baker NA, McCammon JA. Optimizing the Poisson dielectric boundary with explicit solvent forces and energies: lessons learned With atomcentered dielectric functions. J Chem Theory Comput, 3, 170183, 2007. (http://dx.doi.org/10.1021/ ct600216k) to nonpolar forces to address this issue. > Can I expect the nonpolar energies resulting from your > algorithms to be consistent with the electrostatic energies > I get from PB calculations (provided of course the > PB parameters, radii, charges, epsilon_P are appropriate) No, not necessarily. We mainly released these algorithms based on user requests  not because we have complete sets of parameters for them. Any new systems will definitely require testing and possibly reparameterization. > Talking about PB parameters, I've done some work > comparing binding energies from PB calculations combined with > simple DeltaSASA based nonpolar energies, Notwithstanding the > known shortcomings of the latter model, did you find any particular > set of PB parameters  e.g. Bondi vs Parse vs some, possibly > scaled, force field based radii, or AM1BCC vs force field based > charges, etc  to perform better than others ? No  based on our force analysis, all SASA methods performed very badly for a variety of radii. > In my, but small, test set CHARMm based radii plus CHARMm (mind > the lower case m) peptide charges combined with ESP charges for > ligand and epsilon_P=1 seemed to perform best, closely followed > by the parameters suggested by Nina and Roux, 1997. However, both > these two, and a number of other parameter sets/combinations I > tried did NOT provide really satisfactory results in terms of > reproducing experimental binding affinities. > Again, this might be due to the poor model for the nonpolar > terms. Considering this it is, of course, very important > to improve such nonpolar models, as you did in your recent > publication  and I wonder if, from this work, you gained any > insights into not only nonpolar forces, but also in the > appropriate parameterization of PB models ? The paper I cited above might have what you're looking for. Note that one of the conclusions of the paper was that splinebased dielectric definitions have some potential caveats  this is important to keep in mind when comparing to more detailed models! Thanks, Nathan  Associate Professor, Dept. of Biochemistry and Molecular Biophysics Center for Computational Biology, Washington University in St. Louis Web: http://cholla.wustl.edu/ 
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