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), pK_A calculations, 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 enth

SUBMITTER: Schauperl M 

PROVIDER: S-EPMC5331458 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature