Entropy–enthalpy transduction caused by conformational shifts can obscure the forces driving protein–ligand binding

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 49; pp. 20006 - 20011
• Main Authors: Fenley, Andrew T, Muddana, Hari S, Gilson, Michael K
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 04.12.2012; National Acad Sciences
• Subjects: Animals; Aprotinin - chemistry; Aprotinin - metabolism; Binding sites; Biological Sciences; calorimetry; Calorimetry - methods; Cattle; Control variables; Enthalpy; Entropy; Free energy; Ligands; Models, Molecular; Molecular dynamics; Molecular Dynamics Simulation; Protein Binding; Protein Conformation; Proteins; Signal transduction; Signal Transduction - physiology; Simulation; Solvents; Statistical mechanics; Thermodynamics; trypsin inhibitors; variance
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1213180109

Molecular dynamics simulations of unprecedented duration now can provide new insights into biomolecular mechanisms. Analysis of a 1-ms molecular dynamics simulation of the small protein bovine pancreatic trypsin inhibitor reveals that its main conformations have different thermodynamic profiles and that perturbation of a single geometric variable, such as a torsion angle or interresidue distance, can select for occupancy of one or another conformational state. These results establish the basis for a mechanism that we term entropy–enthalpy transduction (EET), in which the thermodynamic character of a local perturbation, such as enthalpic binding of a small molecule, is camouflaged by the thermodynamics of a global conformational change induced by the perturbation, such as a switch into a high-entropy conformational state. It is noted that EET could occur in many systems, making measured entropies and enthalpies of folding and binding unreliable indicators of actual thermodynamic driving forces. The same mechanism might also account for the high experimental variance of measured enthalpies and entropies relative to free energies in some calorimetric studies. Finally, EET may be the physical mechanism underlying many cases of entropy–enthalpy compensation.