Quantitatively characterizing the ligand binding mechanisms of choline binding protein using Markov state model...

Area of Science:

• Biochemistry
• Computational Biology
• Structural Biology

Background:

• Protein-ligand recognition is crucial for biological processes.
• Mechanisms involve induced fit and conformational selection.
• Choline binding protein (ChoX) is a model system.

Purpose of the Study:

• To elucidate the dominant mechanism in protein-ligand recognition.
• To quantify the contributions of induced fit versus conformational selection.
• To characterize the conformational states of choline binding protein (ChoX).

Main Methods:

• Developed a novel three-pronged approach.
• Integrated Markov State Models (MSMs) and Molecular Dynamics (MD) simulations.
• Employed flux analysis combined with experimental data.

Main Results:

• Quantified choline binding protein (ChoX) recognition as ~90% conformational selection dominant.
• Identified multiple metastable conformational states for ChoX.
• Confirmed the dominance of an apo-closed state, aligning with prior experimental findings.

Conclusions:

• The developed methodology accurately quantifies recognition mechanisms.
• Conformational selection is the primary driver for ChoX-ligand binding.
• This approach has broad applicability for studying fundamental biological recognition processes.