Protein dimerization in 2D vs 3D: Geometric allostery enhances binding affinity.

Area of Science:

• Biophysics
• Structural Biology
• Computational Biology

Background:

• Dimerization is fundamental to macromolecular assembly in both solution (3D) and on membrane surfaces (2D).
• The ratio of dissociation constants (h) determines dimerization preference between 3D and 2D environments.
• Rigid-body estimates of h are often used, but protein flexibility can alter dimerization thermodynamics.

Purpose of the Study:

• To investigate the impact of protein flexibility on BAR domain dimerization stability in 2D versus 3D environments.
• To determine if surface-induced allostery enhances 2D dimerization compared to rigid-body predictions.
• To assess the necessity of explicit lipid bilayers for observing 2D dimerization stabilization.

Main Methods:

• Molecular dynamics (MD) simulations of BAR homodimerization.
• Simulations conducted in solution (3D), on a lipid bilayer (2D), and in a solvated pseudo-membrane environment (2D).
• Analysis of free energy landscapes and enthalpic contributions to dimerization stability.

Main Results:

• Protein flexibility significantly alters the free energy landscape, enhancing native dimer stability in 2D environments.
• Both explicit lipid bilayers and solvated pseudo-membranes induced configurations favoring enthalpically stable 2D dimers.
• Surface-induced allostery was observed, leading to h values significantly lower than rigid-body estimates (h ≪ hRIGID).
• The observed stabilization effect was dependent on the intrinsic stability of the 3D protein interaction.

Conclusions:

• Moderate flexibility in BAR domains dramatically enhances dimerization stability on membrane surfaces compared to solution.
• Geometric allostery, driven by surface interactions, stabilizes 2D dimerization beyond rigid-body predictions.
• Explicit lipid bilayers are not essential for observing surface-induced stabilization of protein dimerization.