Thread: [Apbs-users] non-binders results
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From: Dimitrios S. <dim...@gm...> - 2009-09-16 15:47:03
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Dear APBS users, I'm performing a computational alanine scanning of a complex (without considering the entropic term, so far): some of the protein mutants I'm investigating show no binding by means of experimental techniques. I expected that the free energy variations of these mutants compared to the wild type protein would be very positive. Instead, I found out that these "non-binding" mutants tend to have null variations of free energy compared to the wild type. I then tried to perform separate MD simulations for each mutant, and the results are very similar, thus these results do not seem to be related to the computational alanine scanning approach. Thus, I'd say they could be outliers. Is it possible that the predictability of MM/PBSA for the interaction of two non binding molecular species is low, possibly due to the somewhat irrealistic nature of the simulated complex? Thank you very much in advance! Dimitrios Spiliotopoulos _________________________________________________________________________________________________ Dulbecco Telethon Institute c/o DIBIT Scientific Institute Biomolecular NMR Laboratory, 1B4 Via Olgettina 58, 20132 Milano (Italy) Tel : 0039-0226434348/5622/3497/4922 Fax : 0039-0226434153 Email : spi...@hs...; dim...@gm... Skype: dimitris3.16 |
From: Nathan B. <ba...@bi...> - 2009-09-18 00:51:48
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Hello -- > I'm performing a computational alanine scanning of a complex > (without considering the entropic term, so far): Just to clarify: are you only including polar/nonpolar solvation and molecular mechanical contributions in your calculations? Do you see any variation, even if it's weak? Thanks, Nathan > some of the protein mutants I'm investigating show no binding by > means of experimental techniques. > I expected that the free energy variations of these mutants compared > to the wild type protein would be very positive. Instead, I found > out that these "non-binding" mutants tend to have null variations of > free energy compared to the wild type. > I then tried to perform separate MD simulations for each mutant, and > the results are very similar, thus these results do not seem to be > related to the computational alanine scanning approach. Thus, I'd > say they could be outliers. > > Is it possible that the predictability of MM/PBSA for the > interaction of two non binding molecular species is low, possibly > due to the somewhat irrealistic nature of the simulated complex? > > Thank you very much in advance! > > Dimitrios Spiliotopoulos > _________________________________________________________________________________________________ > Dulbecco Telethon Institute c/o DIBIT Scientific Institute > Biomolecular NMR Laboratory, 1B4 > Via Olgettina 58, 20132 Milano (Italy) > Tel : 0039-0226434348/5622/3497/4922 > Fax : 0039-0226434153 > Email : spi...@hs...; dim...@gm... > Skype: dimitris3.16 > > ------------------------------------------------------------------------------ > Come build with us! The BlackBerry® Developer Conference in SF, CA > is the only developer event you need to attend this year. Jumpstart > your > developing skills, take BlackBerry mobile applications to market and > stay > ahead of the curve. Join us from November 9-12, 2009. Register > now! > http://p.sf.net/sfu/devconf_______________________________________________ > apbs-users mailing list > apb...@li... > https://lists.sourceforge.net/lists/listinfo/apbs-users — Nathan Baker (ba...@bi...) Associate Professor, Dept. of Biochemistry and Molecular Biophysics Director, Computational and Molecular Biophysics Graduate Program Center for Computational Biology, Washington University in St. Louis Web: http://bakergroup.wustl.edu/ |
From: Dimitrios S. <dim...@gm...> - 2009-09-18 09:28:43
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Dear prof Baker, in my calculations I consider coulombic, Lennard-Jones, polar/nonpolar solvation (it is what Massova and Kollman called "subtotal free energy variation"). In the following, I pasted the values of the mean and the standard deviations obtained from the analysis of 51 frames (the values, both the mean and in parentheses the standard deviations, are expressed in kcal/mol; the wt is expected to have a binding energy equal to -7.03 kcal/mol, none of the following mutants binds the ligand) coulombic LJ polar solvation apolar solvation wt -939.64 (47.21) -26.98 (27.23) -96.72 (27.32) -301.76 (11.12) mut1 -929.45 (48.51) -53.49 (5.06) -96.99 (25.33) -297.39 (11.06) mut2 -771.78 (46.49) -45.51 (4.91) -112.83 (22.59) -263.24 (11.74) mut3 -936.14 (43.06) -25.09 (25.93) -79.37 (31.22) -284.55 (10.95) so that the "subtotal free energy variations" are SFEV (subtotal free energy variations) wt -1365.10 (112.89) mut1 -1377.32 (89.97) mut2 -1193.36 (85.74) mut3 -1325.16 (112.17) Thank you very much in advance! d. _________________________________________________________________________________________________ Dulbecco Telethon Institute c/o DIBIT Scientific Institute Biomolecular NMR Laboratory, 1B4 Via Olgettina 58, 20132 Milano (Italy) Tel : 0039-0226434348/5622/3497/4922 Fax : 0039-0226434153 Email : spi...@hs...; dim...@gm... Skype: dimitris3.16 2009/9/17 Nathan Baker <ba...@bi...> > Hello -- > > I'm performing a computational alanine scanning of a complex (without > considering the entropic term, so far): > > > Just to clarify: are you only including polar/nonpolar solvation and > molecular mechanical contributions in your calculations? Do you see any > variation, even if it's weak? > > Thanks, > > Nathan > > some of the protein mutants I'm investigating show no binding by means of > experimental techniques. > I expected that the free energy variations of these mutants compared to the > wild type protein would be very positive. Instead, I found out that these > "non-binding" mutants tend to have null variations of free energy compared > to the wild type. > I then tried to perform separate MD simulations for each mutant, and the > results are very similar, thus these results do not seem to be related to > the computational alanine scanning approach. Thus, I'd say they could be > outliers. > > Is it possible that the predictability of MM/PBSA for the interaction of > two non binding molecular species is low, possibly due to the somewhat > irrealistic nature of the simulated complex? > > Thank you very much in advance! > > Dimitrios Spiliotopoulos > > _________________________________________________________________________________________________ > Dulbecco Telethon Institute c/o DIBIT Scientific Institute > Biomolecular NMR Laboratory, 1B4 > Via Olgettina 58, 20132 Milano (Italy) > Tel : 0039-0226434348/5622/3497/4922 > Fax : 0039-0226434153 > Email : spi...@hs...; dim...@gm... > Skype: dimitris3.16 > > > ------------------------------------------------------------------------------ > Come build with us! The BlackBerry® Developer Conference in SF, CA > is the only developer event you need to attend this year. Jumpstart your > developing skills, take BlackBerry mobile applications to market and stay > ahead of the curve. Join us from November 9-12, 2009. Register now! > http://p.sf.net/sfu/devconf_______________________________________________ > apbs-users mailing list > apb...@li... > https://lists.sourceforge.net/lists/listinfo/apbs-users > > > — > Nathan Baker (ba...@bi...) > Associate Professor, Dept. of Biochemistry and Molecular Biophysics > Director, Computational and Molecular Biophysics Graduate Program > Center for Computational Biology, Washington University in St. Louis > Web: http://bakergroup.wustl.edu/ > > > > > > > > > > > > > > > > > |
From: Nathan B. <ba...@bi...> - 2009-09-19 15:47:04
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Hello -- These variations are certainly within the range that one might expect from these types of calculations. If they don't agree with experiment, then I would suspect something more fundamental about the accuracy/appropriateness of the calculation methodology to this type of problem. -- Nathan On Sep 18, 2009, at 4:28 AM, Dimitrios Spiliotopoulos wrote: > > Dear prof Baker, > > in my calculations I consider coulombic, Lennard-Jones, polar/ > nonpolar solvation (it is what Massova and Kollman called "subtotal > free energy variation"). In the following, I pasted the values of > the mean and the standard deviations obtained from the analysis of > 51 frames (the values, both the mean and in parentheses the standard > deviations, are expressed in kcal/mol; the wt is expected to have a > binding energy equal to -7.03 kcal/mol, none of the following > mutants binds the ligand) > > coulombic LJ > polar solvation apolar solvation > > wt -939.64 (47.21) -26.98 (27.23) > -96.72 (27.32) -301.76 (11.12) > mut1 -929.45 (48.51) -53.49 (5.06) -96.99 > (25.33) -297.39 (11.06) > mut2 -771.78 (46.49) -45.51 (4.91) -112.83 > (22.59) -263.24 (11.74) > mut3 -936.14 (43.06) -25.09 (25.93) -79.37 > (31.22) -284.55 (10.95) > > so that the "subtotal free energy variations" are > > SFEV (subtotal free energy variations) > > wt -1365.10 (112.89) > mut1 -1377.32 (89.97) > mut2 -1193.36 (85.74) > mut3 -1325.16 (112.17) > > Thank you very much in advance! > > d. > > _________________________________________________________________________________________________ > Dulbecco Telethon Institute c/o DIBIT Scientific Institute > Biomolecular NMR Laboratory, 1B4 > Via Olgettina 58, 20132 Milano (Italy) > Tel : 0039-0226434348/5622/3497/4922 > Fax : 0039-0226434153 > Email : spi...@hs...; dim...@gm... > Skype: dimitris3.16 > > > > > 2009/9/17 Nathan Baker <ba...@bi...> > Hello -- > >> I'm performing a computational alanine scanning of a complex >> (without considering the entropic term, so far): > > Just to clarify: are you only including polar/nonpolar solvation > and molecular mechanical contributions in your calculations? Do you > see any variation, even if it's weak? > > Thanks, > > Nathan > >> some of the protein mutants I'm investigating show no binding by >> means of experimental techniques. >> I expected that the free energy variations of these mutants >> compared to the wild type protein would be very positive. Instead, >> I found out that these "non-binding" mutants tend to have null >> variations of free energy compared to the wild type. >> I then tried to perform separate MD simulations for each mutant, >> and the results are very similar, thus these results do not seem to >> be related to the computational alanine scanning approach. Thus, >> I'd say they could be outliers. >> >> Is it possible that the predictability of MM/PBSA for the >> interaction of two non binding molecular species is low, possibly >> due to the somewhat irrealistic nature of the simulated complex? >> >> Thank you very much in advance! >> >> Dimitrios Spiliotopoulos >> _________________________________________________________________________________________________ >> Dulbecco Telethon Institute c/o DIBIT Scientific Institute >> Biomolecular NMR Laboratory, 1B4 >> Via Olgettina 58, 20132 Milano (Italy) >> Tel : 0039-0226434348/5622/3497/4922 >> Fax : 0039-0226434153 >> Email : spi...@hs...; dim...@gm... >> Skype: dimitris3.16 >> >> ------------------------------------------------------------------------------ >> Come build with us! The BlackBerry® Developer Conference in SF, >> CA >> is the only developer event you need to attend this year. Jumpstart >> your >> developing skills, take BlackBerry mobile applications to market >> and stay >> ahead of the curve. Join us from November 9-12, 2009. Register >> now! >> http://p.sf.net/sfu/devconf_______________________________________________ >> apbs-users mailing list >> apb...@li... >> https://lists.sourceforge.net/lists/listinfo/apbs-users > > — > Nathan Baker (ba...@bi...) > Associate Professor, Dept. of Biochemistry and Molecular Biophysics > Director, Computational and Molecular Biophysics Graduate Program > Center for Computational Biology, Washington University in St. Louis > Web: http://bakergroup.wustl.edu/ > > > > > > > > > > > > > > > > > — Nathan Baker (ba...@bi...) Associate Professor, Dept. of Biochemistry and Molecular Biophysics Director, Computational and Molecular Biophysics Graduate Program Center for Computational Biology, Washington University in St. Louis Web: http://bakergroup.wustl.edu/ |