Insights into the Loop at the E-Selectin Binding Site: From Open to Close Conformation

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• E-selectin and sialyl Lewis x (sLe^x) interactions are crucial for leukocyte recruitment and inflammation.
• The E-selectin binding site loop exhibits open and closed conformations, influencing molecular interactions.
• The dynamic role of these loop conformations in selectin/sLe^x binding remains incompletely understood.

Purpose of the Study:

• To investigate the functional impact of E-selectin binding site loop conformations on sialyl Lewis x (sLe^x) interactions.
• To elucidate the atomic and dynamic mechanisms governing E-selectin/sLe^x binding and dissociation.
• To understand how loop dynamics contribute to leukocyte adhesion and inflammatory processes.

Main Methods:

• Molecular dynamics (MD) simulations were employed to study loop dynamics.
• Adaptive steered MD simulations were utilized to probe binding and dissociation pathways.
• Energy calculations, including potential mean force (PMF), quantified interaction strengths.

Main Results:

• The E-selectin binding site loop spontaneously transitions from an open to a closed conformation upon sLe^x binding.
• The closed loop conformation enhances sLe^x binding by increasing immersion depth within the binding site.
• Dissociation of sLe^x from the closed loop conformation requires greater energy, promoting catch bond formation and extended interaction lifetimes.

Conclusions:

• E-selectin loop conformation plays a critical role in modulating the affinity and duration of sLe^x interactions.
• The dynamic conformational switch enhances the stability of E-selectin/sLe^x binding, impacting leukocyte adhesion.
• This study provides detailed insights into the molecular mechanisms underlying selectin-mediated cell adhesion and inflammation.