Molecular Dynamics Simulation Study on Allosteric Regulation of CD44-Hyaluronan Binding as a Force Sensing Mechanism

Area of Science:

• Biophysics
• Molecular Biology
• Cellular Mechanics

Background:

• CD44 protein, a cell surface receptor for hyaluronan (HA), mediates cell adhesion and leukocyte trafficking.
• External mechanical forces can induce conformational changes in CD44, shifting it from an ordered (O) to a partially disordered (PD) state.
• The PD conformation exhibits higher HA affinity than the O conformation, but the underlying force-sensing mechanics remain unclear.

Purpose of the Study:

• To elucidate the allosteric regulation of HA binding to CD44 through conformational shifts.
• To investigate the role of mechanical force in modulating CD44-HA interactions using molecular dynamics simulations.

Main Methods:

• Classical molecular dynamics simulations were employed to model the CD44 HA binding domain.
• Simulations analyzed conformational changes (O to PD) induced by external mechanical force.
• HA-binding affinities of different CD44 conformations were assessed.

Main Results:

• The ordered (O) conformation is thermodynamically favored at equilibrium and exhibits weak HA-binding affinity.
• External force-induced partially disordered (PD) conformation can refold into a compact structure that retains bound HA.
• This refolded conformation demonstrates significantly higher HA-binding affinity compared to both O and PD states.

Conclusions:

• External mechanical force allosterically regulates HA affinity by inducing unfolding in a disordered region remote from the binding site.
• This mechanism provides novel insights into CD44-mediated cell rolling and force-induced allosteric regulation.
• Understanding these dynamics is crucial for comprehending cell adhesion and trafficking processes.