Nano-motion Dynamics are Determined by Surface-Tethered Selectin Mechanokinetics and Bond Formation 英文参考文献.docVIP

Nano-motionDynamicsareDeterminedby Surface-TetheredSelectinMechanokinetics andBondFormation BrianJ.Schmidt,JasonA.Papin,MichaelB.Lawrence* DepartmentofBiomedicalEngineering,UniversityofVirginia,Charlottesville,Virginia,UnitedStatesofAmerica Abstract Theinteractionofproteinsatcellularinterfacesiscriticalformanybiologicalprocesses,fromintercellularsignalingtocell adhesion.Forexample,theselectinfamilyofadhesionreceptorsplaysacriticalroleintraffickingduringinflammationand immunosurveillance.Quantitativemeasurementsofbindingratesbetweensurface-constrainedproteinselicitinsightinto howmolecularstructuraldetailsandpost-translationalmodificationscontributetofunction.However,nano-scaletransport effectscanobfuscatemeasurementsinexperimentalassays.Weconstructedabiophysicalsimulationofthemotionofa rigid microsphere coated with biomolecular adhesion receptors in shearing flow undergoing thermal motion. The simulation enabled in silico investigation of the effects of kinetic force dependence, molecular deformation, grouping adhesion receptors into clusters, surface-constrained bond formation, and nano-scale vertical transport on outputs that directlymaptoobservablemotions.Simulationsrecreatedthejerky,discretestop-and-gomotionsobservedinP-selectin/ PSGL-1 microbead assays with physiologic ligand densities. Motion statistics tied detailed simulated motion data to experimentally reported quantities. New deductions about biomolecular function for P-selectin/PSGL-1 interactions were made.DistributingadhesiveforcesamongP-selectin/PSGL-1moleculescloselygroupedinclusterswasnecessarytoachieve bond lifetimes observed in microbead assays. Initial, capturing bond formation effectively occurred across the entire molecular contour length. However, subsequent rebinding events were enhanced by the reduced separation distance following the initial capture. The result demonstrates that vertical transport can contribute to an enhancement in the apparentbondformationrate.Adetailedanalysisofinsilico