Enhanced Permeability of Charged Dendrimers across Tense Lipid Bilayer Membranes

Dendrimers have successfully proved themselves as functional nanodevices for drug delivery because they can render drug molecules a greater water solubility, bioavailability, and biocompatibility. It has recently been suggested that the structural changes of cell membranes (e.g., local lipid density and actual pore or hole) could affect the permeability across them for dendrimers. However, to understand these effects requires direct measurements in a single cell and is thus very difficult and more challenging. Here we use mesoscopic simulations to investigate the tension-mediated complexes comprising charged dendrimers and lipid bilayer membranes. The structures of membranes are alternated by adjusting their surface tensions. Our simulations demonstrate that the permeability of charged dendrimers can be effectively enhanced in the tense membranes, and the permeability in the actual hole is several times higher than that in the lipid-poor section. The possible mechanism of charged dendrimer-induced pore nucleation in the tense membranes is evaluated. The findings have implications in tuning intracellular delivery rates and amounts in nanoscale complex and chemotherapeutics

Charged Dendrimers on Lipid Bilayer Membranes: Insight through Dissipative Particle Dynamics Simulations

Understanding the interactions of dendrimers with biological membranes is of fundamental importance in determining their potential biomedical applications like drug delivery vehicles and gene therapeutic agents. Herein we perform systematically mesoscopic simulations to investigate the interactions and binding structures in complexes comprised of charged dendrimers with lipid bilayer membranes. For these purposes, various interaction strengths between the outer-dendrimer hydrophilic component and lipid heads and those between the inner-dendrimer hydrophobic component and lipid tails are used in the simulations. The external force is also induced into the complexes by stretching the membranes to examine the influence of the dendrimer binding on the stabilization of the lipid bilayer membranes. Our simulations demonstrate that the increasing attraction between outer dendrimer and lipid heads leads to wider spread of dendrimer along the membrane surface, while the attraction between the inner dendrimer and lipid tails has a great effect on the insertion of the dendrimer into the bilayer membrane. It is found that the dendrimer can induce a hole in the tense bilayer membrane at earlier time for a stronger attraction between the hydrophobic dendrimer component and lipid tails, which prompts the failure of the membrane affected by the external forces or surroundings. The findings could provide some guidelines for the design of the dendrimers with defined molecular architectures and prompt the understanding for the stabilization of the tense membranes and the potential cytotoxicity of the charged dendrimers in the dendrimer−lipid bilayer membrane complexes

Enhanced Permeability of Charged Dendrimers across Tense Lipid Bilayer Membranes

Dendrimers have successfully proved themselves as functional nanodevices for drug delivery because they can render drug molecules a greater water solubility, bioavailability, and biocompatibility. It has recently been suggested that the structural changes of cell membranes (e.g., local lipid density and actual pore or hole) could affect the permeability across them for dendrimers. However, to understand these effects requires direct measurements in a single cell and is thus very difficult and more challenging. Here we use mesoscopic simulations to investigate the tension-mediated complexes comprising charged dendrimers and lipid bilayer membranes. The structures of membranes are alternated by adjusting their surface tensions. Our simulations demonstrate that the permeability of charged dendrimers can be effectively enhanced in the tense membranes, and the permeability in the actual hole is several times higher than that in the lipid-poor section. The possible mechanism of charged dendrimer-induced pore nucleation in the tense membranes is evaluated. The findings have implications in tuning intracellular delivery rates and amounts in nanoscale complex and chemotherapeutics

Enhanced Permeability of Charged Dendrimers across Tense Lipid Bilayer Membranes

Dendrimers have successfully proved themselves as functional nanodevices for drug delivery because they can render drug molecules a greater water solubility, bioavailability, and biocompatibility. It has recently been suggested that the structural changes of cell membranes (e.g., local lipid density and actual pore or hole) could affect the permeability across them for dendrimers. However, to understand these effects requires direct measurements in a single cell and is thus very difficult and more challenging. Here we use mesoscopic simulations to investigate the tension-mediated complexes comprising charged dendrimers and lipid bilayer membranes. The structures of membranes are alternated by adjusting their surface tensions. Our simulations demonstrate that the permeability of charged dendrimers can be effectively enhanced in the tense membranes, and the permeability in the actual hole is several times higher than that in the lipid-poor section. The possible mechanism of charged dendrimer-induced pore nucleation in the tense membranes is evaluated. The findings have implications in tuning intracellular delivery rates and amounts in nanoscale complex and chemotherapeutics

Enhanced Permeability of Charged Dendrimers across Tense Lipid Bilayer Membranes

Dendrimers have successfully proved themselves as functional nanodevices for drug delivery because they can render drug molecules a greater water solubility, bioavailability, and biocompatibility. It has recently been suggested that the structural changes of cell membranes (e.g., local lipid density and actual pore or hole) could affect the permeability across them for dendrimers. However, to understand these effects requires direct measurements in a single cell and is thus very difficult and more challenging. Here we use mesoscopic simulations to investigate the tension-mediated complexes comprising charged dendrimers and lipid bilayer membranes. The structures of membranes are alternated by adjusting their surface tensions. Our simulations demonstrate that the permeability of charged dendrimers can be effectively enhanced in the tense membranes, and the permeability in the actual hole is several times higher than that in the lipid-poor section. The possible mechanism of charged dendrimer-induced pore nucleation in the tense membranes is evaluated. The findings have implications in tuning intracellular delivery rates and amounts in nanoscale complex and chemotherapeutics

Charged Dendrimers on Lipid Bilayer Membranes: Insight through Dissipative Particle Dynamics Simulations

Understanding the interactions of dendrimers with biological membranes is of fundamental importance in determining their potential biomedical applications like drug delivery vehicles and gene therapeutic agents. Herein we perform systematically mesoscopic simulations to investigate the interactions and binding structures in complexes comprised of charged dendrimers with lipid bilayer membranes. For these purposes, various interaction strengths between the outer-dendrimer hydrophilic component and lipid heads and those between the inner-dendrimer hydrophobic component and lipid tails are used in the simulations. The external force is also induced into the complexes by stretching the membranes to examine the influence of the dendrimer binding on the stabilization of the lipid bilayer membranes. Our simulations demonstrate that the increasing attraction between outer dendrimer and lipid heads leads to wider spread of dendrimer along the membrane surface, while the attraction between the inner dendrimer and lipid tails has a great effect on the insertion of the dendrimer into the bilayer membrane. It is found that the dendrimer can induce a hole in the tense bilayer membrane at earlier time for a stronger attraction between the hydrophobic dendrimer component and lipid tails, which prompts the failure of the membrane affected by the external forces or surroundings. The findings could provide some guidelines for the design of the dendrimers with defined molecular architectures and prompt the understanding for the stabilization of the tense membranes and the potential cytotoxicity of the charged dendrimers in the dendrimer−lipid bilayer membrane complexes

Image_9_Phylogenetic and AlphaFold predicted structure analyses provide insights for A1 aspartic protease family classification in Arabidopsis.tif

Aspartic proteases are widely distributed in animals, plants, fungi and other organisms. In land plants, A1 aspartic protease family members have been implicated to play important and varied roles in growth, development and defense. Thus a robust classification of this family is important for understanding their gene function and evolution. However, current A1 family members in Arabidopsis are less well classified and need to be re-evaluated. In this paper, 70 A1 aspartic proteases in Arabidopsis are divided into four groups (group I-IV) based on phylogenetic and gene structure analyses of 1200 A1 aspartic proteases which are obtained from 12 Embryophyta species. Group I-III members are further classified into 2, 4 and 7 subgroups based on the AlphaFold predicted structures. Furthermore, unique insights of A1 aspartic proteases have been unraveled by AlphaFold predicted structures. For example, subgroup II-C members have a unique II-C specific motif in the C-extend domain, and subgroup IV is a Spermatophyta conserved group without canonical DTGS/DSGT active sites. These results prove that AlphaFold combining phylogenetic analysis is a promising solution for complex gene family classification.</p

Image_1_Phylogenetic and AlphaFold predicted structure analyses provide insights for A1 aspartic protease family classification in Arabidopsis.tif

Aspartic proteases are widely distributed in animals, plants, fungi and other organisms. In land plants, A1 aspartic protease family members have been implicated to play important and varied roles in growth, development and defense. Thus a robust classification of this family is important for understanding their gene function and evolution. However, current A1 family members in Arabidopsis are less well classified and need to be re-evaluated. In this paper, 70 A1 aspartic proteases in Arabidopsis are divided into four groups (group I-IV) based on phylogenetic and gene structure analyses of 1200 A1 aspartic proteases which are obtained from 12 Embryophyta species. Group I-III members are further classified into 2, 4 and 7 subgroups based on the AlphaFold predicted structures. Furthermore, unique insights of A1 aspartic proteases have been unraveled by AlphaFold predicted structures. For example, subgroup II-C members have a unique II-C specific motif in the C-extend domain, and subgroup IV is a Spermatophyta conserved group without canonical DTGS/DSGT active sites. These results prove that AlphaFold combining phylogenetic analysis is a promising solution for complex gene family classification.</p

Table_3_Phylogenetic and AlphaFold predicted structure analyses provide insights for A1 aspartic protease family classification in Arabidopsis.xlsx

Aspartic proteases are widely distributed in animals, plants, fungi and other organisms. In land plants, A1 aspartic protease family members have been implicated to play important and varied roles in growth, development and defense. Thus a robust classification of this family is important for understanding their gene function and evolution. However, current A1 family members in Arabidopsis are less well classified and need to be re-evaluated. In this paper, 70 A1 aspartic proteases in Arabidopsis are divided into four groups (group I-IV) based on phylogenetic and gene structure analyses of 1200 A1 aspartic proteases which are obtained from 12 Embryophyta species. Group I-III members are further classified into 2, 4 and 7 subgroups based on the AlphaFold predicted structures. Furthermore, unique insights of A1 aspartic proteases have been unraveled by AlphaFold predicted structures. For example, subgroup II-C members have a unique II-C specific motif in the C-extend domain, and subgroup IV is a Spermatophyta conserved group without canonical DTGS/DSGT active sites. These results prove that AlphaFold combining phylogenetic analysis is a promising solution for complex gene family classification.</p

Presentation_1_Phylogenetic and AlphaFold predicted structure analyses provide insights for A1 aspartic protease family classification in Arabidopsis.zip

Aspartic proteases are widely distributed in animals, plants, fungi and other organisms. In land plants, A1 aspartic protease family members have been implicated to play important and varied roles in growth, development and defense. Thus a robust classification of this family is important for understanding their gene function and evolution. However, current A1 family members in Arabidopsis are less well classified and need to be re-evaluated. In this paper, 70 A1 aspartic proteases in Arabidopsis are divided into four groups (group I-IV) based on phylogenetic and gene structure analyses of 1200 A1 aspartic proteases which are obtained from 12 Embryophyta species. Group I-III members are further classified into 2, 4 and 7 subgroups based on the AlphaFold predicted structures. Furthermore, unique insights of A1 aspartic proteases have been unraveled by AlphaFold predicted structures. For example, subgroup II-C members have a unique II-C specific motif in the C-extend domain, and subgroup IV is a Spermatophyta conserved group without canonical DTGS/DSGT active sites. These results prove that AlphaFold combining phylogenetic analysis is a promising solution for complex gene family classification.</p