The distribution of Al （j） and the structural units distribution of Qi T in calcium aluminosilicate melts were studied by means of molecular dynamics simulation. The results show that provided there exists lower-fie...The distribution of Al （j） and the structural units distribution of Qi T in calcium aluminosilicate melts were studied by means of molecular dynamics simulation. The results show that provided there exists lower-field strength cation relative to Al3+, such as alkaline and alkaline earth metals, Al will be four-coordinated but not six-coordinated. Meanwhile, if there exist a large number of higher-field strength cations such as Si4+ and little lower-field strength cation, six-coordinated aluminum will be formed. The relation of structural units distribution of Qi T with chemical composition shift was also extracted, showing that as Ca2+ exists, the distributions of Qi Si, Qi Al or Qi T have the similar changing trend with the variation of component. Because of high-temperature effect, the Al-tetrahedral units in melts are greatly active and unstable and there exist dynamic transforming equilibria of Al（3）Al（4） and （Al（5））Al（4）. The three-coordinated oxygen and charge-compensated bridging oxygen are proposed to explain phenomena of the negative charge redundancy of AlO4 and location of network modifier with charge-compensated function in aluminosilicate melts.展开更多
This study was designed to develop hypothetical inhibition mechanism of novel UT-B inhibitor and exploit novel compounds with UT-B inhibitory activity and to obtain promising lead compounds. We integrated cell based h...This study was designed to develop hypothetical inhibition mechanism of novel UT-B inhibitor and exploit novel compounds with UT-B inhibitory activity and to obtain promising lead compounds. We integrated cell based high throughput screening and in silico method to identify an undiscovered UT-B inhibitor binding site and proposed the mechanism of UT-B inhibitor in cross-species. We employed high-throughput screening using an erythrocyte os- motic lysis assay and identified 4 compounds PU21, PU168, PU468 and PU474 with UT-B inhibitory activity in vitro from 2319 hits. 16 compounds with UT-B inhibitory activity were screened by erythrocyte osmotic lysis assay from 60 analogues of PU21. PU14, one of 16 compounds exhibited potential inhibition activity in human, rabbit, rat, mouse in vitro and pharmacological diuresis activity in vivo. Based on the physiological data, we built a compu- tational mode of human UT-B by homology modeling. The putative UT-B binding site was identified by structure- based drug design and validated by ligand-based and QSAR model. Additionally, UT-B structural and functional differences under inhibitors treated and untreated conditions were simulated by Molecular Dynamics （MD）. The UT-B inhibitor binding site analysis and validation provide structure basses for lead identification and optimization.展开更多
Nanograins are characterized by a typical grain size from 1 to 100 nm. Molecular dynamics simulations have been carried out for the nanograin sphere with the diameters from 1.45 to 10.12 nm. We study the influence of ...Nanograins are characterized by a typical grain size from 1 to 100 nm. Molecular dynamics simulations have been carried out for the nanograin sphere with the diameters from 1.45 to 10.12 nm. We study the influence of grain size on structure and diffusion properties of the nanograins. The results reveal that as the grain size is reduced, the fraction of grain surface increases significantly, and the surface width is approximately constant; the mean atomic energy of the surface increases distinctly, but that of the grain interior varies insignificantly; the diffusion coefficient is increased sharply, and the relation of the diffusion coefficient and the grain size is close to exponential relation below 10 nm.展开更多
Integrin activation,the transition from a low to a high affinity state,regulates the numerous cellular responses consequent to integrin engagement by extracellular matrix proteins.Kindlin proteins,play crucial roles i...Integrin activation,the transition from a low to a high affinity state,regulates the numerous cellular responses consequent to integrin engagement by extracellular matrix proteins.Kindlin proteins,play crucial roles in the integrin-signaling pathway by directly interacting with and activating integrins,which mediate the cell-extracellular matrix adhesion and signaling.As a widely distributed PTB domain protein and a major member of the kindlin family,kindlin2 interacts withβ3-tail,bridges talin-activated integrins to promote integrin aggregation,and enhances talin-induced integrin activation.Thus,kindlin2 is identified as a coactivator of integrins.Unlike talins,kindlin2 cannot directly alter the conformation of the integrin transmembrane helix and fail to activate integrin alone.Nevertheless,although it is widely accepted that kindlins and talins synergistically promote integrin activation,the underlying mechanism is unclear.Thus,the study of the force dissociation of the kindlin2/β3-tail complex and the conformation stabilization under different mechanical micro-environments should be of great significance for the further understanding of the structural basis of its synergistically activation of integrin.To reveal the molecular dynamics mechanism of interaction between kindlin2 andβ3-tail,we perform molecular dynamics(MD)simulations for this complex with different computing strategies interaction.In MD simulations,the available crystal structures of Kindlin-2/β3-tail complex(Protein Data Bank code 5XQ1)was downloaded from the PDB database.Two software packages,VMD for visualization and modeling and NAMD 2.13 for energy minimizations and MD simulations,were used here.The steadystate conformation of the complex was obtained from the equilibrium simulation.The dissociation event was observed by the constant velocity simulation,and the mechanical stability of the complex was observed by the constant force simulation.Our results showed that,during the equilibrium of the kindlin2-F3/β34ail complex,the residue MET612,LYS613 and TRP615 on the F3 domain of kindlin2 contributed to hydrogen-bonding with the corresponding residues onβ3 integrin.These bonds exhibit moderate or strong stability through steered molecular dynamics(SMD)simulation.During the constant velocity simulation,the complex exhibits a variety of unfolding pathways against tension applications,which are mainly distinguished by the disruption of hydrogen-bonds between the F3 domain a1/a2 helixes andβ1/β2 sheets.During the constant force simulation,the different phases of the composite force dissociation have different dissociation probabilities,which shows the biphasic force-dependent characteristics.And,the key residues in the pulling were recognized according not only to the number of interacting residue pairs,but also to their bond strength.Using molecular dynamics simulation,we showed the steady state of the kindlin2-F3/β3-tail complex under different tensile forces,and observe the dynamic process of molecular interaction.A possible underlying biophysical mechanism is that,the dissociation of Kindlin2-F3/β3-tail complex is biphasic force-dependent,and the conformations under different stretching states have different binding affinities.This study not only provides insights into the structural basis and mechanical regulation mechanisms of the kindlin/integrin interaction,in understanding in kindlin/integrin-related signaling in different cellular biological processes,but also provides new ideas for novel drug design and the treatment of related diseases.展开更多
文摘The distribution of Al （j） and the structural units distribution of Qi T in calcium aluminosilicate melts were studied by means of molecular dynamics simulation. The results show that provided there exists lower-field strength cation relative to Al3+, such as alkaline and alkaline earth metals, Al will be four-coordinated but not six-coordinated. Meanwhile, if there exist a large number of higher-field strength cations such as Si4+ and little lower-field strength cation, six-coordinated aluminum will be formed. The relation of structural units distribution of Qi T with chemical composition shift was also extracted, showing that as Ca2+ exists, the distributions of Qi Si, Qi Al or Qi T have the similar changing trend with the variation of component. Because of high-temperature effect, the Al-tetrahedral units in melts are greatly active and unstable and there exist dynamic transforming equilibria of Al（3）Al（4） and （Al（5））Al（4）. The three-coordinated oxygen and charge-compensated bridging oxygen are proposed to explain phenomena of the negative charge redundancy of AlO4 and location of network modifier with charge-compensated function in aluminosilicate melts.
文摘This study was designed to develop hypothetical inhibition mechanism of novel UT-B inhibitor and exploit novel compounds with UT-B inhibitory activity and to obtain promising lead compounds. We integrated cell based high throughput screening and in silico method to identify an undiscovered UT-B inhibitor binding site and proposed the mechanism of UT-B inhibitor in cross-species. We employed high-throughput screening using an erythrocyte os- motic lysis assay and identified 4 compounds PU21, PU168, PU468 and PU474 with UT-B inhibitory activity in vitro from 2319 hits. 16 compounds with UT-B inhibitory activity were screened by erythrocyte osmotic lysis assay from 60 analogues of PU21. PU14, one of 16 compounds exhibited potential inhibition activity in human, rabbit, rat, mouse in vitro and pharmacological diuresis activity in vivo. Based on the physiological data, we built a compu- tational mode of human UT-B by homology modeling. The putative UT-B binding site was identified by structure- based drug design and validated by ligand-based and QSAR model. Additionally, UT-B structural and functional differences under inhibitors treated and untreated conditions were simulated by Molecular Dynamics （MD）. The UT-B inhibitor binding site analysis and validation provide structure basses for lead identification and optimization.
基金supported by the National Naturl Science Foundation of China(No.10172088)the Potdoctoral Saience Foundation of China
文摘Nanograins are characterized by a typical grain size from 1 to 100 nm. Molecular dynamics simulations have been carried out for the nanograin sphere with the diameters from 1.45 to 10.12 nm. We study the influence of grain size on structure and diffusion properties of the nanograins. The results reveal that as the grain size is reduced, the fraction of grain surface increases significantly, and the surface width is approximately constant; the mean atomic energy of the surface increases distinctly, but that of the grain interior varies insignificantly; the diffusion coefficient is increased sharply, and the relation of the diffusion coefficient and the grain size is close to exponential relation below 10 nm.
基金supported by the National Natural Science Foundation of China ( 116272109, 11432006)
文摘Integrin activation,the transition from a low to a high affinity state,regulates the numerous cellular responses consequent to integrin engagement by extracellular matrix proteins.Kindlin proteins,play crucial roles in the integrin-signaling pathway by directly interacting with and activating integrins,which mediate the cell-extracellular matrix adhesion and signaling.As a widely distributed PTB domain protein and a major member of the kindlin family,kindlin2 interacts withβ3-tail,bridges talin-activated integrins to promote integrin aggregation,and enhances talin-induced integrin activation.Thus,kindlin2 is identified as a coactivator of integrins.Unlike talins,kindlin2 cannot directly alter the conformation of the integrin transmembrane helix and fail to activate integrin alone.Nevertheless,although it is widely accepted that kindlins and talins synergistically promote integrin activation,the underlying mechanism is unclear.Thus,the study of the force dissociation of the kindlin2/β3-tail complex and the conformation stabilization under different mechanical micro-environments should be of great significance for the further understanding of the structural basis of its synergistically activation of integrin.To reveal the molecular dynamics mechanism of interaction between kindlin2 andβ3-tail,we perform molecular dynamics(MD)simulations for this complex with different computing strategies interaction.In MD simulations,the available crystal structures of Kindlin-2/β3-tail complex(Protein Data Bank code 5XQ1)was downloaded from the PDB database.Two software packages,VMD for visualization and modeling and NAMD 2.13 for energy minimizations and MD simulations,were used here.The steadystate conformation of the complex was obtained from the equilibrium simulation.The dissociation event was observed by the constant velocity simulation,and the mechanical stability of the complex was observed by the constant force simulation.Our results showed that,during the equilibrium of the kindlin2-F3/β34ail complex,the residue MET612,LYS613 and TRP615 on the F3 domain of kindlin2 contributed to hydrogen-bonding with the corresponding residues onβ3 integrin.These bonds exhibit moderate or strong stability through steered molecular dynamics(SMD)simulation.During the constant velocity simulation,the complex exhibits a variety of unfolding pathways against tension applications,which are mainly distinguished by the disruption of hydrogen-bonds between the F3 domain a1/a2 helixes andβ1/β2 sheets.During the constant force simulation,the different phases of the composite force dissociation have different dissociation probabilities,which shows the biphasic force-dependent characteristics.And,the key residues in the pulling were recognized according not only to the number of interacting residue pairs,but also to their bond strength.Using molecular dynamics simulation,we showed the steady state of the kindlin2-F3/β3-tail complex under different tensile forces,and observe the dynamic process of molecular interaction.A possible underlying biophysical mechanism is that,the dissociation of Kindlin2-F3/β3-tail complex is biphasic force-dependent,and the conformations under different stretching states have different binding affinities.This study not only provides insights into the structural basis and mechanical regulation mechanisms of the kindlin/integrin interaction,in understanding in kindlin/integrin-related signaling in different cellular biological processes,but also provides new ideas for novel drug design and the treatment of related diseases.
