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Unraveling Entropic Rate Acceleration Induced by Solvent Dynamics in Membrane Enzymes

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Binding Pose Flip Explained via Enthalpic and Entropic Contributions.

Michael Schauperl¹, Paul Czodrowski², Julian E Fuchs¹

¹Institute of General, Inorganic and Theoretical Chemistry, and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck , Innrain 80-82, 6020 Innsbruck, Tyrol, Austria.

Journal of Chemical Information and Modeling

|January 13, 2017

Summary

This summary is machine-generated.

Molecular dynamics simulations reveal how TIE2 inhibitor fragments adopt different binding poses. Changes in binding are explained by steric effects, ligand protonation, and thermodynamic contributions like solvation entropy and enthalpic interactions.

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Area of Science:

Biochemistry
Computational Chemistry
Structural Biology

Background:

TIE2 inhibitors are crucial for targeting diseases.
Understanding fragment binding modes is key to drug design.
Similar fragments can exhibit distinct binding behaviors.

Purpose of the Study:

To investigate anomalous binding modes of TIE2 inhibitor fragments.
To provide a quantitative explanation for observed binding pose variations.
To elucidate the thermodynamic drivers behind different binding modes.

Main Methods:

Molecular dynamics (MD) simulations.
Grid Inhomogeneous Solvation Theory (GIST) analysis.
pK_A calculations and enthalpic difference analysis.

Main Results:

Identified three distinct binding poses for five highly similar TIE2 inhibitor fragments.
Rationalized binding pose flips due to steric repulsion and altered ligand protonation states.
Demonstrated that binding poses are determined by either solvation entropy or enthalpic interactions.

Conclusions:

Unprecedented details on binding mode flipping mechanisms were elucidated.
Thermodynamic contributions (solvation entropy vs. enthalpic interactions) dictate binding pose stability.
Findings provide a clear explanation for experimental observations in TIE2 inhibitor systems.