Pore-forming peptides have promising potentials for biomedical uses due to their ability to permeabilize cell membranes.However,to molecularly engineer them for practical applications is still blocked by the poor unde...Pore-forming peptides have promising potentials for biomedical uses due to their ability to permeabilize cell membranes.However,to molecularly engineer them for practical applications is still blocked by the poor understanding of the specific roles of individual residues in peptides’activity.Herein,using an advanced computational approach that combines Coarse-Grained molecular dynamics and well-tempered metadynamics,the membrane activities of melittin,a representative pore-forming peptide,and its gain-of-function variants,are characterized from the kinetics and thermodynamics perspectives.Unbiased simulations elucidate the molecular details of peptide-induced membrane poration;during which,some vital intermediate states,including the aggregation and U-shape configuration formation of peptides in the membrane,are observed and further applied as collective variables to construct the multi-dimensional free energy landscapes of the peptide-membrane interactions.Such a combination of kinetic and thermodynamic descriptions of the interaction process provides crucial information of residue-specialized contribution in chain conformation and consequently membrane perforation ability of the peptide.It is found that residues at the kink part(e.g.Thr)determine the chain flexibility and U-shape bending of the peptide,while residues near the C-terminus(e.g.Arg and Lys)are responsible for recruiting neighboring peptides for inter-molecular cooperation;the probable reaction pathway and the poration efficiency are consequently regulated.These results are helpful for a comprehensive understanding of the complicated molecular mechanism of pore-forming peptides and pave the way to rationally design and/or engineer the peptides for practical applications.展开更多
Imaging-guided cancer therapy provides a simultaneous tumor imaging and treatment, which helps to eliminate the excessive toxicity to the healthy tissues. For this purpose, multifunctional probes capable of both imagi...Imaging-guided cancer therapy provides a simultaneous tumor imaging and treatment, which helps to eliminate the excessive toxicity to the healthy tissues. For this purpose, multifunctional probes capable of both imaging and curing are needed. In this work, we synthesize water-soluble silicon quantum dots（Si QDs） smaller than 5 nm. Such Si QDs are used for delivering the hydrophobic drug phthalocyanine（Pc）. The as-prepared Si/Pc nanocomposite particles show efficient transmembrane delivery into cells and feasible biocompatibility. Moreover, these composite particles emit dualchannel fluorescence signals even after cellular internalization and demonstrate robust photostability in the Si channel.More interestingly, the Si/Pc composite particles show efficient photodynamic therapy effects against tumors both in vitro and in vivo.展开更多
Lateral heterogeneity of a cell membrane,including the formation of lipid raft-like clusters and the inter-leaflet coupling of specific phase domains,is crucial for cellular functions such as membrane trafficking and ...Lateral heterogeneity of a cell membrane,including the formation of lipid raft-like clusters and the inter-leaflet coupling of specific phase domains,is crucial for cellular functions such as membrane trafficking and transmembrane signaling.However,the wide diversity in lipid species and the consequent complexity in lipid-lipid interplays hinder our understanding of the underlying mechanism.In this work,with coarse-grained molecular dynamics simulations,the effect of lipid tail structures on the phase behavior of a model ternary lipid membrane was systematically explored.A serial of 27 lipid membrane systems consisting of saturated,unsaturated lipids,and cholesterol(Chol)molecules,at a fixed molar ratio of 4:4:2 while varying in lipid structures including tail length,unsaturation degree,and/or position of unsaturated atoms,were constructed.These structural factors were found to exert sophisticated influences on packing states of the constituent molecules,especially Chol,in a bilayer,and modulate the complicated entropy-enthalpy competition of the membrane system accordingly.Specifically,an appropriate difference in effective tail length and distinct feature of the tail ends between the saturated and unsaturated lipid compositions promised an enhanced phase separation of the membrane into the Chol-rich Lo and Chol-poor Ld phase domains,with a full inter-leaflet coupling of each domain.Our results provide insights into the lipid organizations and segregations of the cellular plasma membrane.展开更多
基金Supported by the National Natural Science Foundation of China under Grant Nos.21422404,21774092,U1532108,and 21728502the Priority Academic Program Development(PAPD)of Jiangsu Higher Education Institutionsthe Natural Science Foundation of Jiangsu Province of China under Grant Nos.BK20171207 and BK20171210
文摘Pore-forming peptides have promising potentials for biomedical uses due to their ability to permeabilize cell membranes.However,to molecularly engineer them for practical applications is still blocked by the poor understanding of the specific roles of individual residues in peptides’activity.Herein,using an advanced computational approach that combines Coarse-Grained molecular dynamics and well-tempered metadynamics,the membrane activities of melittin,a representative pore-forming peptide,and its gain-of-function variants,are characterized from the kinetics and thermodynamics perspectives.Unbiased simulations elucidate the molecular details of peptide-induced membrane poration;during which,some vital intermediate states,including the aggregation and U-shape configuration formation of peptides in the membrane,are observed and further applied as collective variables to construct the multi-dimensional free energy landscapes of the peptide-membrane interactions.Such a combination of kinetic and thermodynamic descriptions of the interaction process provides crucial information of residue-specialized contribution in chain conformation and consequently membrane perforation ability of the peptide.It is found that residues at the kink part(e.g.Thr)determine the chain flexibility and U-shape bending of the peptide,while residues near the C-terminus(e.g.Arg and Lys)are responsible for recruiting neighboring peptides for inter-molecular cooperation;the probable reaction pathway and the poration efficiency are consequently regulated.These results are helpful for a comprehensive understanding of the complicated molecular mechanism of pore-forming peptides and pave the way to rationally design and/or engineer the peptides for practical applications.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.21374074,21422404,and U1532108)the Undergraduate Training Program for Innovation and Entrepreneurship of Soochow University,China(Grant No.2016xj010)
文摘Imaging-guided cancer therapy provides a simultaneous tumor imaging and treatment, which helps to eliminate the excessive toxicity to the healthy tissues. For this purpose, multifunctional probes capable of both imaging and curing are needed. In this work, we synthesize water-soluble silicon quantum dots（Si QDs） smaller than 5 nm. Such Si QDs are used for delivering the hydrophobic drug phthalocyanine（Pc）. The as-prepared Si/Pc nanocomposite particles show efficient transmembrane delivery into cells and feasible biocompatibility. Moreover, these composite particles emit dualchannel fluorescence signals even after cellular internalization and demonstrate robust photostability in the Si channel.More interestingly, the Si/Pc composite particles show efficient photodynamic therapy effects against tumors both in vitro and in vivo.
基金Project supported by the National Natural Science Foundation of China (Grant Nos. 21422404,21774092,U1532108,21728502,and U1932121)the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions+1 种基金the support of the Natural Science Foundation of Jiangsu Province of China (Grant Nos. BK20171207 and BK20171210)the support of Undergraduate Training Program for Innovation and Entrepreneurship of Soochow University,China (Grant No. 201810285023Z)
文摘Lateral heterogeneity of a cell membrane,including the formation of lipid raft-like clusters and the inter-leaflet coupling of specific phase domains,is crucial for cellular functions such as membrane trafficking and transmembrane signaling.However,the wide diversity in lipid species and the consequent complexity in lipid-lipid interplays hinder our understanding of the underlying mechanism.In this work,with coarse-grained molecular dynamics simulations,the effect of lipid tail structures on the phase behavior of a model ternary lipid membrane was systematically explored.A serial of 27 lipid membrane systems consisting of saturated,unsaturated lipids,and cholesterol(Chol)molecules,at a fixed molar ratio of 4:4:2 while varying in lipid structures including tail length,unsaturation degree,and/or position of unsaturated atoms,were constructed.These structural factors were found to exert sophisticated influences on packing states of the constituent molecules,especially Chol,in a bilayer,and modulate the complicated entropy-enthalpy competition of the membrane system accordingly.Specifically,an appropriate difference in effective tail length and distinct feature of the tail ends between the saturated and unsaturated lipid compositions promised an enhanced phase separation of the membrane into the Chol-rich Lo and Chol-poor Ld phase domains,with a full inter-leaflet coupling of each domain.Our results provide insights into the lipid organizations and segregations of the cellular plasma membrane.
