A model of crosslinker unbinding is implemented in a highly coarse- grained granular model of F-actin cytoskeleton. We employ this specific granular model to study the mechanisms of the compressive responses of F-acti...A model of crosslinker unbinding is implemented in a highly coarse- grained granular model of F-actin cytoskeleton. We employ this specific granular model to study the mechanisms of the compressive responses of F-actin networks. It is found that the compressive response of F-actin cytoskeleton has dependency on the strain rate. The evolution of deformation energy in the network indicates that crosslinker unbinding events can induce the remodelling of F-actin cytoskele- ton in response to external loadings. The internal stress in F-actin cytoskeleton can efficiently dissipate with the help of crosslinker unbinding, which could lead to the soontaneous relaxation of living cells.展开更多
Mechanical force plays a critical role in the remodeling and degradation of cartilage tissues.The cartilage tissue generates,absorbs,and transmits mechanical force,enabling specific biological processes in our body.A ...Mechanical force plays a critical role in the remodeling and degradation of cartilage tissues.The cartilage tissue generates,absorbs,and transmits mechanical force,enabling specific biological processes in our body.A moderate intensity mechanical force is necessary for cartilage tissue remodeling and the adaptation of biomechanical properties,but a high intensity mechanical force can lead to pathological degradation of cartilage tissue.However,the molecular mechanism of cartilage degradation is still unclear.We use full atomistic simulations with SMD simulations to investigate whether the magnitude of mechanical force affects the unbinding pathway of the MMP8-Aggrecan_IGD complex.We find that when the pulling velocity is slow,the mechanical force required to unbind the Aggrecan_IGD from MMP8 is higher,and a three-step unbinding pathway is observed.On the other hand,when the pulling velocity is fast,the mechanical force required to unbind the Aggrecan_IGD from MMP8 is lower,and a two-step unbinding pathway is observed.Our results help us to understand how the magnitude of the mechanical force affects the unbinding pathway of the enzyme-ligand complex in cartilage tissue at the molecular level.展开更多
Dichloromethane(DCM)dehalogenase stands as a crucial enzyme implicated in the degradation of methylene chloride across diverse environmental and biological contexts.However,the unbinding pathways of ligands from DCM d...Dichloromethane(DCM)dehalogenase stands as a crucial enzyme implicated in the degradation of methylene chloride across diverse environmental and biological contexts.However,the unbinding pathways of ligands from DCM dehalogenase remain unexplored.In order to gain a deeper understanding of the binding sites and dissociation pathways of dichloromethane(DCM)and glutathione(GSH)from the DCM dehalogenase,random accelerated molecular dynamics(RAMD)simulations were performed,in which DCM and GSH were forced to leave the active site.The protein structure was predicted using Alphafold2,and the conformations of GSH and DCM in the binding pocket were predicted by docking.A long equilibrium simulation was conducted to validate the structure of the complex.The results show that GSH is most commonly observed in three main pathways,one of which is more important than the other two.In addition,DCM was observed to escape along a unique pathway.The key residues and protein helices of each pathway were identified.The results can provide a theoretical foundation for the subsequent dissociation mechanism of DCM dehalogenase.展开更多
We study an exclusion process with multiple dynamic roadblocks.Each roadblock can move diffusively forward or backward with different rates,as well as unbind from/rebind to a free site.By Monte Carlo simulations,the t...We study an exclusion process with multiple dynamic roadblocks.Each roadblock can move diffusively forward or backward with different rates,as well as unbind from/rebind to a free site.By Monte Carlo simulations,the two moving types are investigated in combination of roadblock number.The case of only diffusive roadblocks shows an asymmetric current-density relation.The case of only long-range jumping roadblocks presents that flux decreases with increasing roadblock number.展开更多
基金supported by the ARC Future Fellowship Grant(FT100100172)
文摘A model of crosslinker unbinding is implemented in a highly coarse- grained granular model of F-actin cytoskeleton. We employ this specific granular model to study the mechanisms of the compressive responses of F-actin networks. It is found that the compressive response of F-actin cytoskeleton has dependency on the strain rate. The evolution of deformation energy in the network indicates that crosslinker unbinding events can induce the remodelling of F-actin cytoskele- ton in response to external loadings. The internal stress in F-actin cytoskeleton can efficiently dissipate with the help of crosslinker unbinding, which could lead to the soontaneous relaxation of living cells.
文摘Mechanical force plays a critical role in the remodeling and degradation of cartilage tissues.The cartilage tissue generates,absorbs,and transmits mechanical force,enabling specific biological processes in our body.A moderate intensity mechanical force is necessary for cartilage tissue remodeling and the adaptation of biomechanical properties,but a high intensity mechanical force can lead to pathological degradation of cartilage tissue.However,the molecular mechanism of cartilage degradation is still unclear.We use full atomistic simulations with SMD simulations to investigate whether the magnitude of mechanical force affects the unbinding pathway of the MMP8-Aggrecan_IGD complex.We find that when the pulling velocity is slow,the mechanical force required to unbind the Aggrecan_IGD from MMP8 is higher,and a three-step unbinding pathway is observed.On the other hand,when the pulling velocity is fast,the mechanical force required to unbind the Aggrecan_IGD from MMP8 is lower,and a two-step unbinding pathway is observed.Our results help us to understand how the magnitude of the mechanical force affects the unbinding pathway of the enzyme-ligand complex in cartilage tissue at the molecular level.
基金National Natural Science Foundation of China(22073030)the Oriental Scholars of Shanghai Universities。
文摘Dichloromethane(DCM)dehalogenase stands as a crucial enzyme implicated in the degradation of methylene chloride across diverse environmental and biological contexts.However,the unbinding pathways of ligands from DCM dehalogenase remain unexplored.In order to gain a deeper understanding of the binding sites and dissociation pathways of dichloromethane(DCM)and glutathione(GSH)from the DCM dehalogenase,random accelerated molecular dynamics(RAMD)simulations were performed,in which DCM and GSH were forced to leave the active site.The protein structure was predicted using Alphafold2,and the conformations of GSH and DCM in the binding pocket were predicted by docking.A long equilibrium simulation was conducted to validate the structure of the complex.The results show that GSH is most commonly observed in three main pathways,one of which is more important than the other two.In addition,DCM was observed to escape along a unique pathway.The key residues and protein helices of each pathway were identified.The results can provide a theoretical foundation for the subsequent dissociation mechanism of DCM dehalogenase.
基金Project supported by the National Basic Research Program of China(Grant No.2012CB725404)the National Natural Science Foundation of China(Grant Nos.11422221,71171185,and 71371175)
文摘We study an exclusion process with multiple dynamic roadblocks.Each roadblock can move diffusively forward or backward with different rates,as well as unbind from/rebind to a free site.By Monte Carlo simulations,the two moving types are investigated in combination of roadblock number.The case of only diffusive roadblocks shows an asymmetric current-density relation.The case of only long-range jumping roadblocks presents that flux decreases with increasing roadblock number.
