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J Comput Chem. 2016 Apr 15;37(10):913-9. doi: 10.1002/jcc.24276. Epub 2015 Dec 21.

The role of protein "Stability patches" in molecular recognition: A case study of the human growth hormone-receptor complex.

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Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York.
Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.


Dynamic characteristics of protein surfaces are among the factors determining their functional properties, including their potential participation in protein-protein interactions. The presence of clusters of static residues-"stability patches" (SPs)-is a characteristic of protein surfaces involved in intermolecular recognition. The mechanism, by with SPs facilitate molecular recognition, however, remains unclear. Analyzing the surface dynamic properties of the growth hormone and of its high-affinity variant we demonstrated that reshaping of the SPs landscape may be among the factors accountable for the improved affinity of this variant to the receptor. We hypothesized that SPs facilitate molecular recognition by moderating the conformational entropy of the unbound state, diminishing enthalpy-entropy compensation upon binding, and by augmenting the favorable entropy of desolvation. SPs mapping emerges as a valuable tool for investigating the structural basis of the stability of protein complexes and for rationalizing experimental approaches, such as affinity maturation, aimed at improving it.


affinity maturation; desolvation; enthalpy-entropy compensation; growth hormone; growth hormone receptor; hydration layer; protein-protein interaction; solvation energy; stability patches; steered molecular dynamics simulation

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