title: Binding Pose Flip Explained via Enthalpic and Entropic Contributions.
abstract: The anomalous binding modes of five highly similar fragments of TIE2 inhibitors, showing three distinct binding poses, are investigated. We report a quantitative rationalization for the changes in binding pose based on molecular dynamics simulations. We investigated five fragments in complex with the transforming growth factor β receptor type 1 kinase domain. Analyses of these simulations using Grid Inhomogeneous Solvation Theory (GIST), pKAcalculations, and a tool to investigate enthalpic differences upon binding unraveled the various thermodynamic contributions to the different binding modes. While one binding mode flip can be rationalized by steric repulsion, the second binding pose flip revealed a different protonation state for one of the ligands, leading to different enthalpic and entropic contributions to the binding free energy. One binding pose is stabilized by the displacement of entropically unfavored water molecules (binding pose determined by solvation entropy), ligands in the other binding pose are stabilized by strong enthalpic interactions, overcompensating the unfavorable water entropy in this pose (binding pose determined by enthalpic interactions). This analysis elucidates unprecedented details determining the flipping of the binding modes, which can elegantly explain the experimental findings for this system.
authors.affiliation: Institute of General, Inorganic and Theoretical Chemistry, and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck , Innrain 80-82, 6020 Innsbruck, Tyrol, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Schauperl
authors.affiliation: Discovery Technologies, Merck Serono Research, Merck Serono R&D, Merck KGaA , Frankfurter Strasse 250, 64293 Darmstadt, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Czodrowski
authors.affiliation: Institute of General, Inorganic and Theoretical Chemistry, and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck , Innrain 80-82, 6020 Innsbruck, Tyrol, Austria.
authors.forename: Julian E
authors.initials: JE
authors.lastname: Fuchs
authors.affiliation: Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR) , #07-01 Matrix, 30 Biopolis Street, 138671, Singapore.
authors.forename: Roland G
authors.identifier: 0000-0001-5093-5988
authors.initials: RG
authors.lastname: Huber
authors.affiliation: Institute of General, Inorganic and Theoretical Chemistry, and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck , Innrain 80-82, 6020 Innsbruck, Tyrol, Austria.
authors.forename: Birgit J
authors.initials: BJ
authors.lastname: Waldner
authors.affiliation: Institute of General, Inorganic and Theoretical Chemistry, and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck , Innrain 80-82, 6020 Innsbruck, Tyrol, Austria.
authors.forename: Maren
authors.initials: M
authors.lastname: Podewitz
authors.affiliation: Institute of General, Inorganic and Theoretical Chemistry, and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck , Innrain 80-82, 6020 Innsbruck, Tyrol, Austria.
authors.forename: Christian
authors.identifier: 0000-0001-8663-5266
authors.initials: C
authors.lastname: Kramer
authors.affiliation: Institute of General, Inorganic and Theoretical Chemistry, and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck , Innrain 80-82, 6020 Innsbruck, Tyrol, Austria.
authors.forename: Klaus R
authors.identifier: 0000-0002-0985-2299
authors.initials: KR
authors.lastname: Liedl
mesh_terms: D055808:Drug Discovery; D019277:Entropy; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D000072417:Protein Domains; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012997:Solvents / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D012997:Solvents; D014867:Water; D042787:Receptor, TIE-2