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 : spiliotopoulos.dimitrios@hsr.it; dimitris3.16@gmail.com
Skype: dimitris3.16





2009/9/17 Nathan Baker <baker@biochem.wustl.edu>
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 : spiliotopoulos.dimitrios@hsr.it; dimitris3.16@gmail.com
Skype: dimitris3.16


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Associate Professor, Dept. of Biochemistry and Molecular Biophysics
Director, Computational and Molecular Biophysics Graduate Program
Center for Computational Biology, Washington University in St. Louis