Volume 13, Issue 1
In Silico Investigation of pH-Dependence of Prolactin and Human Growth Hormone Binding to Human Prolactin Receptor

Lin Wang, Shawn Witham, Zhe Zhang, Lin Li, Michael Hodsdon & Emil Alexov

Commun. Comput. Phys., 13 (2013), pp. 207-222.

Published online: 2013-01

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  • Abstract

Experimental data shows that the binding of human prolactin (hPRL) to human prolactin receptor (hPRLr-ECD) is strongly pH-dependent, while the binding of the same receptor to human growth hormone (hGH) is pH-independent. Here we carry in silico analysis of the molecular effects causing such a difference and reveal the role of individual amino acids. It is shown that the computational modeling correctly predicts experimentally determined pKa’s of histidine residues in an unbound state in the majority of the cases and the pH-dependence of the binding free energy. Structural analysis carried in conjunction with calculated pH-dependence of the binding revealed that the main reason for pH-dependence of the binding of hPRL-hPRLr-ECD is anumberof salt-bridgesacrosstheinterfaceof thecomplex, while nosalt-bridgesare formed in the hGH-hPRlr-ECD. Specifically, most of the salt-bridges involve histidine residues and this is the reason for the pH-dependence across a physiological range of pH. The analysis not only revealed the molecular mechanism of the pH-dependence of the hPRL-hPRLr-ECD, but also provided critical insight into the underlying physicchemical mechanism.


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@Article{CiCP-13-207, author = {Lin Wang, Shawn Witham, Zhe Zhang, Lin Li, Michael Hodsdon and Emil Alexov}, title = {In Silico Investigation of pH-Dependence of Prolactin and Human Growth Hormone Binding to Human Prolactin Receptor}, journal = {Communications in Computational Physics}, year = {2013}, volume = {13}, number = {1}, pages = {207--222}, abstract = {

Experimental data shows that the binding of human prolactin (hPRL) to human prolactin receptor (hPRLr-ECD) is strongly pH-dependent, while the binding of the same receptor to human growth hormone (hGH) is pH-independent. Here we carry in silico analysis of the molecular effects causing such a difference and reveal the role of individual amino acids. It is shown that the computational modeling correctly predicts experimentally determined pKa’s of histidine residues in an unbound state in the majority of the cases and the pH-dependence of the binding free energy. Structural analysis carried in conjunction with calculated pH-dependence of the binding revealed that the main reason for pH-dependence of the binding of hPRL-hPRLr-ECD is anumberof salt-bridgesacrosstheinterfaceof thecomplex, while nosalt-bridgesare formed in the hGH-hPRlr-ECD. Specifically, most of the salt-bridges involve histidine residues and this is the reason for the pH-dependence across a physiological range of pH. The analysis not only revealed the molecular mechanism of the pH-dependence of the hPRL-hPRLr-ECD, but also provided critical insight into the underlying physicchemical mechanism.


}, issn = {1991-7120}, doi = {https://doi.org/10.4208/cicp.170911.131011s}, url = {http://global-sci.org/intro/article_detail/cicp/7219.html} }
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