Enhanced Sampling Applied to Modeling Allosteric Regulation in Transcription

Area of Science:

• Computational Biology
• Biophysics
• Molecular Dynamics

Background:

• Allosteric regulation by intrinsically disordered proteins (IDPs) governs key cellular functions, including transcription.
• Molecular dynamics (MD) simulations offer insights into IDP-mediated allosteric regulation.
• Calculating binding affinities with MD is challenging due to the rare binding-unbinding events.

Purpose of the Study:

• To present a novel, efficient sampling approach for calculating binding affinities using MD simulations.
• To apply this method to investigate positive allostery in a specific protein complex.

Main Methods:

• Utilized Hamiltonian replica exchange combined with a native-centric coarse-grained model.
• Developed a new sampling strategy to overcome limitations in simulating rare binding events.
• Applied the method to study the CREB binding protein's kinase-inducible domain.

Main Results:

• Accurate and efficient calculation of binding affinities was achieved.
• The new method successfully characterized positive allostery in the studied protein.
• Demonstrated enhanced binding of a second ligand due to a prebound ligand.

Conclusions:

• The developed Hamiltonian replica exchange approach provides an effective means to compute binding affinities.
• This method advances the study of allosteric regulation by intrinsically disordered proteins.
• The findings offer a deeper understanding of molecular interactions in biological systems.