Coarse-grained molecular simulations of allosteric cooperativity

Area of Science:

• Computational Biology
• Biophysics
• Structural Biology

Background:

• Protein-ligand interactions involve conformational changes influencing binding affinity and sensitivity.
• Calmodulin (CaM) binds Ca(2+) ions, a process crucial for cellular signaling.
• Understanding the structural basis of CaM's allosteric cooperativity is key.

Purpose of the Study:

• To investigate the structural origins of binding affinity and allosteric cooperativity for Ca(2+) binding to Calmodulin (CaM).
• To compare the binding characteristics of the N-terminal and C-terminal domains of CaM.
• To model the dynamic response of protein energy landscapes to ligand binding.

Main Methods:

• Simulations of a coarse-grained model for Calmodulin (CaM).
• Explicit simulation of protein conformational transitions (open and closed ensembles).
• Implicit treatment of ligand (Ca(2+)) binding/unbinding within the grand canonical ensemble.

Main Results:

• Ligand binding is cooperative due to coupled binding sites and conformational ensemble shifts.
• The Monod-Wyman-Changeux model accurately describes the simulated binding thermodynamics.
• The C-terminal domain of CaM exhibits higher Ca(2+) binding affinity and cooperativity than the N-terminal domain.

Conclusions:

• Protein dynamics and conformational ensembles are critical for modulating binding affinity and cooperativity.
• Individual binding loop affinity depends on structural compatibility with the ligand and conformational flexibility.
• Distinct structural properties underlie the differential Ca(2+) binding behavior of CaM's domains.