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

In Silico Investigation of pH-Dependence of Prolactin and Human Growth Hormone Binding to Human Prolactin Receptor

Lin Wang 1, Shawn Witham 1, Zhe Zhang 1, Lin Li 1, Michael Hodsdon 2, Emil Alexov 1*

1 Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, SC 29634, USA.
2 Department of Laboratory Medicine and the Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut 06520, USA.

Received 17 September 2011; Accepted (in revised version) 13 October 2011
Available online 12 June 2012


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 a number of salt-bridges across the interface of the complex, while no salt-bridges are 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 physic-chemical mechanism.

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PACS: 82.20.Wt
Key words: Human prolactin, human prolactin receptor, human growth hormone, pKa calculations, pH-dependence, electrostatics.

*Corresponding author.
Email: (L. Wang), (S. Witham), (Z. Zhang), (L. Li), (M. Hodsdon), (E. Alexov)

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