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Hydrogen bonding penalty upon ligand binding.

Zhao H, Huang D - PLoS ONE (2011)

Bottom Line: A new model integrated with hydrogen bonding penalty for free energy calculation gives a root mean square error of 0.7 kcal/mol on 74 inhibitors in the training set and of 1.1 kcal/mol on 64 inhibitors in the test set.Moreover, an application of hydrogen bonding penalty into a high throughput docking campaign for EphB4 inhibitors is presented, and remarkably, three novel scaffolds are discovered out of seven tested.The binding affinity and ligand efficiency of the most potent compound is about 300 nM and 0.35 kcal/mol per non-hydrogen atom, respectively.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Zurich, Zurich, Switzerland.

ABSTRACT
Ligand binding involves breakage of hydrogen bonds with water molecules and formation of new hydrogen bonds between protein and ligand. In this work, the change of hydrogen bonding energy in the binding process, namely hydrogen bonding penalty, is evaluated with a new method. The hydrogen bonding penalty can not only be used to filter unrealistic poses in docking, but also improve the accuracy of binding energy calculation. A new model integrated with hydrogen bonding penalty for free energy calculation gives a root mean square error of 0.7 kcal/mol on 74 inhibitors in the training set and of 1.1 kcal/mol on 64 inhibitors in the test set. Moreover, an application of hydrogen bonding penalty into a high throughput docking campaign for EphB4 inhibitors is presented, and remarkably, three novel scaffolds are discovered out of seven tested. The binding affinity and ligand efficiency of the most potent compound is about 300 nM and 0.35 kcal/mol per non-hydrogen atom, respectively.

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Comparison of the calculated versus experimental binding energies.A) Training set of 74 inhibitors. R2 = 0.92 and RMS error = 0.69 kcal/mol; B) Validation set of 64 inhibitors. RMS error = 1.12 kcal/mol. The blue dots indicated the 14 p38α inhibitors with one formal charge. The green diagonal line is the ideal line of perfect prediction. The black diagonals delimit the 1 kcal/mol error region.
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pone-0019923-g003: Comparison of the calculated versus experimental binding energies.A) Training set of 74 inhibitors. R2 = 0.92 and RMS error = 0.69 kcal/mol; B) Validation set of 64 inhibitors. RMS error = 1.12 kcal/mol. The blue dots indicated the 14 p38α inhibitors with one formal charge. The green diagonal line is the ideal line of perfect prediction. The black diagonals delimit the 1 kcal/mol error region.

Mentions: The calculated binding energies show high correlation with the experimental values (R-square of 0.92) and a small RMS error of 0.69 kcal/mol (Figure 3A). Here, the parameter β corresponds to the unit hydrogen bonding energy. Notably, the fitted value 1.72 kcal/mol is in agreement with the experimental value, e.g., breakage of a neutral hydrogen bond resulting in loss of energy from 0.5 to 1.5 kcal/mol [21]. Moreover, a charged primary amine or carboxyl group has a hydrogen bonding weight of 1.5 or 2.0, which can lead to a maximal penalty of 2.58 or 3.44 kcal/mol upon loss of the hydrogen bond/salt bridge. This value also agrees well with the experimental data (up to 4 kcal/mol) [21]. Hydrogen bonding weights were further used to rank the strength of individual hydrogen bonds in DNA base pairs, exhibiting good compatibility with the previously reported results (File S3).


Hydrogen bonding penalty upon ligand binding.

Zhao H, Huang D - PLoS ONE (2011)

Comparison of the calculated versus experimental binding energies.A) Training set of 74 inhibitors. R2 = 0.92 and RMS error = 0.69 kcal/mol; B) Validation set of 64 inhibitors. RMS error = 1.12 kcal/mol. The blue dots indicated the 14 p38α inhibitors with one formal charge. The green diagonal line is the ideal line of perfect prediction. The black diagonals delimit the 1 kcal/mol error region.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3117785&req=5

pone-0019923-g003: Comparison of the calculated versus experimental binding energies.A) Training set of 74 inhibitors. R2 = 0.92 and RMS error = 0.69 kcal/mol; B) Validation set of 64 inhibitors. RMS error = 1.12 kcal/mol. The blue dots indicated the 14 p38α inhibitors with one formal charge. The green diagonal line is the ideal line of perfect prediction. The black diagonals delimit the 1 kcal/mol error region.
Mentions: The calculated binding energies show high correlation with the experimental values (R-square of 0.92) and a small RMS error of 0.69 kcal/mol (Figure 3A). Here, the parameter β corresponds to the unit hydrogen bonding energy. Notably, the fitted value 1.72 kcal/mol is in agreement with the experimental value, e.g., breakage of a neutral hydrogen bond resulting in loss of energy from 0.5 to 1.5 kcal/mol [21]. Moreover, a charged primary amine or carboxyl group has a hydrogen bonding weight of 1.5 or 2.0, which can lead to a maximal penalty of 2.58 or 3.44 kcal/mol upon loss of the hydrogen bond/salt bridge. This value also agrees well with the experimental data (up to 4 kcal/mol) [21]. Hydrogen bonding weights were further used to rank the strength of individual hydrogen bonds in DNA base pairs, exhibiting good compatibility with the previously reported results (File S3).

Bottom Line: A new model integrated with hydrogen bonding penalty for free energy calculation gives a root mean square error of 0.7 kcal/mol on 74 inhibitors in the training set and of 1.1 kcal/mol on 64 inhibitors in the test set.Moreover, an application of hydrogen bonding penalty into a high throughput docking campaign for EphB4 inhibitors is presented, and remarkably, three novel scaffolds are discovered out of seven tested.The binding affinity and ligand efficiency of the most potent compound is about 300 nM and 0.35 kcal/mol per non-hydrogen atom, respectively.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Zurich, Zurich, Switzerland.

ABSTRACT
Ligand binding involves breakage of hydrogen bonds with water molecules and formation of new hydrogen bonds between protein and ligand. In this work, the change of hydrogen bonding energy in the binding process, namely hydrogen bonding penalty, is evaluated with a new method. The hydrogen bonding penalty can not only be used to filter unrealistic poses in docking, but also improve the accuracy of binding energy calculation. A new model integrated with hydrogen bonding penalty for free energy calculation gives a root mean square error of 0.7 kcal/mol on 74 inhibitors in the training set and of 1.1 kcal/mol on 64 inhibitors in the test set. Moreover, an application of hydrogen bonding penalty into a high throughput docking campaign for EphB4 inhibitors is presented, and remarkably, three novel scaffolds are discovered out of seven tested. The binding affinity and ligand efficiency of the most potent compound is about 300 nM and 0.35 kcal/mol per non-hydrogen atom, respectively.

Show MeSH