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Forced dissociation of selectin-ligand complexes using steered molecular dynamics simulation
1National Microgravity Laboratory, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100080, P R China.
Molecular & Cellular Biomechanics : MCB
|May 19, 2006
Summary
Selectin-ligand interactions are vital for inflammation and metastasis. Steered molecular dynamics simulations reveal how bond dissociation links to molecular extension and specific bond breakages, offering insights into adhesion under force.
Area of Science:
- Biophysics
- Molecular Biology
- Computational Chemistry
Background:
- Selectin-ligand interactions mediate critical biological processes like inflammation and tumor metastasis.
- Understanding the atomic-level conformational changes during bond formation and dissociation in blood flow remains a challenge.
Purpose of the Study:
- To elucidate the intramolecular and intermolecular conformational evolutions during the forced dissociation of three selectin-ligand systems using steered molecular dynamics (SMD) simulations.
- To investigate the influence of pulling velocities, forces, and application methods on conformational changes.
Main Methods:
- Utilized steered molecular dynamics (SMD) simulations to analyze forced dissociation of P-selectin lectin (Lec) and epidermal growth factor (EGF)-like domains (P-LE) with synthesized sulfoglycopeptide (SGP-3) and sialyl Lewis X (sLe(X)), and E-selectin Lec-EGF (E-LE) with sLe(X).
- Developed novel force field parameters for carbohydrate units and sulfated tyrosine using an analogy approach.
- Analyzed molecular extension, intramolecular unraveling (EGF domain beta sheets, Lec-EGF interface hydrogen bonds), and intermolecular dissociation (fucose-Ca2+ ion separation).
Main Results:
- Complex dissociation was coupled to molecular extension in all simulated systems.
- Intramolecular unraveling in the P-LE-SGP-3 system involved disruption of EGF beta sheets and hydrogen bonds at the Lec-EGF interface.
- Intermolecular dissociation was primarily driven by the separation of fucose from Ca2+ ions across all three systems.
Conclusions:
- The study provides atomic-level insights into the conformational dynamics of selectin-ligand interactions under external forces.
- Understanding these conformational changes is crucial for deciphering the adhesive functionality of selectins in physiological and pathological processes.
- The findings contribute to a deeper comprehension of molecular mechanisms underlying selectin-mediated cell adhesion.