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J Phys Chem B. 2012 Jun 21;116(24):7168-75. doi: 10.1021/jp303495b. Epub 2012 Jun 4.

Thermodynamic impact of embedded water molecules in the unfolding of human CD2BP2-GYF domain.

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  • 1Department of Physical Chemistry, Biochemistry and Inorganic Chemistry, University of Almeria, Agrifood Campus of International Excellence (ceiA3), Carretera de Sacramento, 04120 Almeria, Spain.

Abstract

GYF domains are small polyproline-recognition modules adopting a structural arrangement consisting of a single α-helix packed against a small β-sheet. Although most families of proline-rich recognition modules have been extensively characterized in terms of function, structure, or conformational flexibility, little is known about GYF domain functionality and folding. We have undertaken the thermodynamic characterization of the unfolding of CD2BP2-GYF domain by combining differential scanning calorimetry and circular dichroism under different pH conditions. The experimental data can be well-described in terms of a two-state equilibrium, although an unusually high heat capacity of the native state reflects a considerable conformational flexibility and dynamics of CD2BP2-GYF domain. In addition, the normalized thermodynamic parameters of unfolding (enthalpy, entropy and heat capacity) are roughly a factor of two greater than expected. In contrast, stability curves reveal an ordinary unfolding behavior of CD2BP2-GYF domain in terms of Gibbs energies, incurring thus unusually strong enthalpy-entropy compensation. This phenomenon, previously described as "thermodynamic homeostasis", has been associated in different examples to the contribution of occluded water (solvent) molecules into the protein structure. By means of CASTp server, we have found seven cavities/pockets scattered throughout of the CD2BP2-GYF structure, each able to harbor at least one water molecule. This structural feature provides rationalization for the atypical enthalpy values observed for CD2BP2-GYF because each water molecule is able to organize an extra amount of hydrogen bonds in the native state. In addition, these bound waters increase the vibrational entropy of the protein, which could also be responsible for an increase in protein flexibility and may thus fully explain the homeostatic behavior experimentally observed.

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