title: Enthalpy-Entropy Compensation upon Molecular Conformational Changes.
abstract: The change in free energy is the dominant factor in all chemical processes; it usually encompasses enthalpy-entropy compensation (EEC). Here, we use the free energy perturbation formalism to show that EEC is influenced by the molecular conformational changes (CCs) of the entire system comprising the solute and by the already known solvent reorganization. The internal changes of enthalpy and the entropy due to CCs upon modifying the interactions (perturbation) cancel each other exactly. The CCs influence the dissipation of the modified interactions and their contributions to the free energy. Using molecular simulations, we show that, for solvation of six different HIV-1 protease inhibitors, CCs in the solute cause EEC as large as 10-30 kcal/mol. Moreover, the EEC due to CCs in HIV-1 protease is shown to vary significantly upon modifying its bound ligand. These findings have important implications for understanding of EEC phenomena and for interpretation of thermodynamic measurements.
authors.affiliation: Department for Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics , Campus E1 4, 66123 Saarbrücken, Germany.
authors.forename: Mazen
authors.initials: M
authors.lastname: Ahmad
authors.affiliation: Center for Bioinformatics, Saarland University , 66123 Saarbrücken, Germany.
authors.forename: Volkhard
authors.initials: V
authors.lastname: Helms
authors.affiliation: Department for Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics , Campus E1 4, 66123 Saarbrücken, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lengauer
authors.affiliation: Department for Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics , Campus E1 4, 66123 Saarbrücken, Germany.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Kalinina
mesh_terms: D019277:Entropy; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1