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On the electrostatic component of protein-protein binding free energy.

Talley K, Ng C, Shoppell M, Kundrotas P, Alexov E - PMC Biophys (2008)

Bottom Line: For instance, the fraction of the homo-complexes, for which the electrostatics was found to oppose binding, is 80% regardless of the force fields and parameters used.Correlations were also found among the results obtained with different force fields.Set of rules of obtaining confident predictions of absolute DeltaDeltaGel and DeltaDeltaGel sign are provided in the conclusion section.PACS codes: 87.15.A-, 87.15. km.

View Article: PubMed Central - HTML - PubMed

Affiliation: Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, SC 29634, USA. ealexov@clemson.edu.

ABSTRACT
Calculations of electrostatic properties of protein-protein complexes are usually done within framework of a model with a certain set of parameters. In this paper we present a comprehensive statistical analysis of the sensitivity of the electrostatic component of binding free energy (DeltaDeltaGel) with respect with different force fields (Charmm, Amber, and OPLS), different values of the internal dielectric constant, and different presentations of molecular surface (different values of the probe radius). The study was done using the largest so far set of entries comprising 260 hetero and 2148 homo protein-protein complexes extracted from a previously developed database of protein complexes (ProtCom). To test the sensitivity of the energy calculations with respect to the structural details, all structures were energy minimized with corresponding force field, and the energies were recalculated. The results indicate that the absolute value of the electrostatic component of the binding free energy (DeltaDeltaGel) is very sensitive to the force field parameters, the minimization procedure, the values of the internal dielectric constant, and the probe radius. Nevertheless our results indicate that certain trends in DeltaDeltaGel behavior are much less sensitive to the calculation parameters. For instance, the fraction of the homo-complexes, for which the electrostatics was found to oppose binding, is 80% regardless of the force fields and parameters used. For the hetero-complexes, however, the percentage of the cases for which electrostatics opposed binding varied from 43% to 85%, depending on the protocol and parameters employed. A significant correlation was found between the effects caused by raising the internal dielectric constant and decreasing the probe radius. Correlations were also found among the results obtained with different force fields. However, despite of the correlations found, the absolute DeltaDeltaGel calculated with different force field parameters could differ more than tens of kcal/mol in some cases. Set of rules of obtaining confident predictions of absolute DeltaDeltaGel and DeltaDeltaGel sign are provided in the conclusion section.PACS codes: 87.15.A-, 87.15. km.

No MeSH data available.


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ΔΔGel calculated with probe radius 0.0A and ε(in) = 2.0 versus ΔΔGel calculated with "standard" probe radius 1.4A and different ε(in): (a) non-minimized hetero-complexes, ε(in) = 8.0. (b) non-minimized homo-complexes, ε(in) = 4.0.
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Figure 4: ΔΔGel calculated with probe radius 0.0A and ε(in) = 2.0 versus ΔΔGel calculated with "standard" probe radius 1.4A and different ε(in): (a) non-minimized hetero-complexes, ε(in) = 8.0. (b) non-minimized homo-complexes, ε(in) = 4.0.

Mentions: The observed similarities of the effects caused by increasing the internal dielectric constant and decreasing the magnitude of the probe radius inspired us to investigate a possible correlation between the ΔΔGel calculated with a "standard" probe radius value but with a high internal dielectric constant and the ΔΔGel calculated with a small probe radius and a "standard" internal dielectric constant. Here by "standard" we mean values that are most frequently reported in the literature. To address such a possibility, the corresponding ΔΔGel for each type of dataset, hetero- and homo-complexes, non-minimized and minimized, were subjected to the following procedure: ΔΔGel calculated with probe radius 0.0A and 'standard" dielectric constant of 2.0 were plotted against ΔΔGel calculated with probe radius 1.4A and ε(in) = 1, 2, 4, 8 and 20. The plot resulting to largest correlation coefficient and a slope close to 1.0 was considered as the best fit. In case of non-minimized hetero-complexes (Fig. 4a) the best fit was obtained at ε(in) = 8.0 (Table 2, first row). In case of non-minimized homo-complexes, the best correlation between the calculations with probe radius of 0.0A and 1.4A was obtained at ε(in) = 4.0 (Fig. 4b and Table 2 third row). The same procedure was applied to minimized structures and the results in terms of the slope of the fitting line and the correlation coefficient are shown in Table 2 for hetero- and homo-complexes. Then the procedure was repeated to find the best fit between ΔΔGel calculated with slightly larger probe radius of 0.5A and 'standard" dielectric constant of 2.0 versus ΔΔGel calculated with probe radius 1.4A and ε(in) = 1, 2, 4, 8 and 20. The best fits in terms of correlation coefficient and slope are reported in Table 2, the last four rows. It can be seen that in some cases, the correlation coefficient reaches 0.87, and in other cases, the slope of the fitting line is close to 1.0. However, neither of the plots resulted in a fitting line slope of 1.0 with a simultaneous correlation coefficient of more than 0.90. Thus, despite the observed correlations, the effects caused by the variations in the magnitude of the internal dielectric constant and the probe radius are, strictly speaking, different and depend on particular cases being considered. Perhaps, more detailed sampling of different internal dielectric constant values could obtain better correlations.


On the electrostatic component of protein-protein binding free energy.

Talley K, Ng C, Shoppell M, Kundrotas P, Alexov E - PMC Biophys (2008)

ΔΔGel calculated with probe radius 0.0A and ε(in) = 2.0 versus ΔΔGel calculated with "standard" probe radius 1.4A and different ε(in): (a) non-minimized hetero-complexes, ε(in) = 8.0. (b) non-minimized homo-complexes, ε(in) = 4.0.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2666630&req=5

Figure 4: ΔΔGel calculated with probe radius 0.0A and ε(in) = 2.0 versus ΔΔGel calculated with "standard" probe radius 1.4A and different ε(in): (a) non-minimized hetero-complexes, ε(in) = 8.0. (b) non-minimized homo-complexes, ε(in) = 4.0.
Mentions: The observed similarities of the effects caused by increasing the internal dielectric constant and decreasing the magnitude of the probe radius inspired us to investigate a possible correlation between the ΔΔGel calculated with a "standard" probe radius value but with a high internal dielectric constant and the ΔΔGel calculated with a small probe radius and a "standard" internal dielectric constant. Here by "standard" we mean values that are most frequently reported in the literature. To address such a possibility, the corresponding ΔΔGel for each type of dataset, hetero- and homo-complexes, non-minimized and minimized, were subjected to the following procedure: ΔΔGel calculated with probe radius 0.0A and 'standard" dielectric constant of 2.0 were plotted against ΔΔGel calculated with probe radius 1.4A and ε(in) = 1, 2, 4, 8 and 20. The plot resulting to largest correlation coefficient and a slope close to 1.0 was considered as the best fit. In case of non-minimized hetero-complexes (Fig. 4a) the best fit was obtained at ε(in) = 8.0 (Table 2, first row). In case of non-minimized homo-complexes, the best correlation between the calculations with probe radius of 0.0A and 1.4A was obtained at ε(in) = 4.0 (Fig. 4b and Table 2 third row). The same procedure was applied to minimized structures and the results in terms of the slope of the fitting line and the correlation coefficient are shown in Table 2 for hetero- and homo-complexes. Then the procedure was repeated to find the best fit between ΔΔGel calculated with slightly larger probe radius of 0.5A and 'standard" dielectric constant of 2.0 versus ΔΔGel calculated with probe radius 1.4A and ε(in) = 1, 2, 4, 8 and 20. The best fits in terms of correlation coefficient and slope are reported in Table 2, the last four rows. It can be seen that in some cases, the correlation coefficient reaches 0.87, and in other cases, the slope of the fitting line is close to 1.0. However, neither of the plots resulted in a fitting line slope of 1.0 with a simultaneous correlation coefficient of more than 0.90. Thus, despite the observed correlations, the effects caused by the variations in the magnitude of the internal dielectric constant and the probe radius are, strictly speaking, different and depend on particular cases being considered. Perhaps, more detailed sampling of different internal dielectric constant values could obtain better correlations.

Bottom Line: For instance, the fraction of the homo-complexes, for which the electrostatics was found to oppose binding, is 80% regardless of the force fields and parameters used.Correlations were also found among the results obtained with different force fields.Set of rules of obtaining confident predictions of absolute DeltaDeltaGel and DeltaDeltaGel sign are provided in the conclusion section.PACS codes: 87.15.A-, 87.15. km.

View Article: PubMed Central - HTML - PubMed

Affiliation: Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, SC 29634, USA. ealexov@clemson.edu.

ABSTRACT
Calculations of electrostatic properties of protein-protein complexes are usually done within framework of a model with a certain set of parameters. In this paper we present a comprehensive statistical analysis of the sensitivity of the electrostatic component of binding free energy (DeltaDeltaGel) with respect with different force fields (Charmm, Amber, and OPLS), different values of the internal dielectric constant, and different presentations of molecular surface (different values of the probe radius). The study was done using the largest so far set of entries comprising 260 hetero and 2148 homo protein-protein complexes extracted from a previously developed database of protein complexes (ProtCom). To test the sensitivity of the energy calculations with respect to the structural details, all structures were energy minimized with corresponding force field, and the energies were recalculated. The results indicate that the absolute value of the electrostatic component of the binding free energy (DeltaDeltaGel) is very sensitive to the force field parameters, the minimization procedure, the values of the internal dielectric constant, and the probe radius. Nevertheless our results indicate that certain trends in DeltaDeltaGel behavior are much less sensitive to the calculation parameters. For instance, the fraction of the homo-complexes, for which the electrostatics was found to oppose binding, is 80% regardless of the force fields and parameters used. For the hetero-complexes, however, the percentage of the cases for which electrostatics opposed binding varied from 43% to 85%, depending on the protocol and parameters employed. A significant correlation was found between the effects caused by raising the internal dielectric constant and decreasing the probe radius. Correlations were also found among the results obtained with different force fields. However, despite of the correlations found, the absolute DeltaDeltaGel calculated with different force field parameters could differ more than tens of kcal/mol in some cases. Set of rules of obtaining confident predictions of absolute DeltaDeltaGel and DeltaDeltaGel sign are provided in the conclusion section.PACS codes: 87.15.A-, 87.15. km.

No MeSH data available.


Related in: MedlinePlus