calmodulin binding protein
; cyclic AMP binding protein
; ligand
; protein
; solvent
; water
; protein
; protein binding
; Article
; binding affinity
; conformational transition
; enthalpy
; entropy
; hydration
; molecular recognition
; priority journal
; protein interaction
; quantitative analysis
; surface area
; temperature
; thermodynamics
; chemistry
; entropy
; nuclear magnetic resonance spectroscopy
; procedures
; protein conformation
; Entropy
; Ligands
; Magnetic Resonance Spectroscopy
; Protein Binding
; Protein Conformation
; Proteins
; Solvents
; Thermodynamics
; Water
英文摘要:
Molecular recognition by proteins is fundamental to molecular biology. Dissection of the thermodynamic energy terms governing protein-ligand interactions has proven difficult, with determination of entropic contributions being particularly elusive. NMR relaxation measurements have suggested that changes in protein conformational entropy can be quantitatively obtained through a dynamical proxy, but the generality of this relationship has not been shown. Twenty-eight protein-ligand complexes are used to show a quantitative relationship between measures of fast side-chain motion and the underlying conformational entropy. We find that the contribution of conformational entropy can range from favorable to unfavorable, which demonstrates the potential of this thermodynamic variable to modulate protein-ligand interactions. For about one-quarter of these complexes, the absence of conformational entropy would render the resulting affinity biologically meaningless. The dynamical proxy for conformational entropy or "entropy meter" also allows for refinement of the contributions of solvent entropy and the loss in rotational-translational entropy accompanying formation of high-affinity complexes. Furthermore, structure-based application of the approach can also provide insight into long-lived specific water-protein interactions that escape the generic treatments of solvent entropy based simply on changes in accessible surface area. These results provide a comprehensive and unified view of the general role of entropy in high-affinity molecular recognition by proteins.
Caro, J.A., Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6059, United States; Harpole, K.W., Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6059, United States; Kasinath, V., Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6059, United States; Lim, J., Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6059, United States; Granja, J., Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6059, United States; Valentine, K.G., Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6059, United States; Sharp, K.A., Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6059, United States; Wand, A.J., Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6059, United States
Recommended Citation:
Caro J.A.,Harpole K.W.,Kasinath V.,et al. Entropy in molecular recognition by proteins[J]. Proceedings of the National Academy of Sciences of the United States of America,2017-01-01,114(25)