Recently,lipid nanoparticles(LNPs)have been extensively investigated as non-viral carriers of nucleic acid vaccines due to their high transport efficiency,safety,and straightforward production and scalability.However,...Recently,lipid nanoparticles(LNPs)have been extensively investigated as non-viral carriers of nucleic acid vaccines due to their high transport efficiency,safety,and straightforward production and scalability.However,the molecular mechanism underlying the interactions between nucleic acids and phospholipid bilayers within LNPs remains elusive.In this study,we employed the all-atom molecular dynamics simulation to investigate the interactions between single-stranded nucleic acids and a phospholipid bilayer.Our findings revealed that hydrophilic bases,specifically G in single-stranded RNA(ssRNA)and single-stranded DNA(ssDNA),displayed a higher propensity to form hydrogen bonds with phospholipid head groups.Notably,ssRNA exhibited stronger binding energy than ssDNA.Furthermore,divalent ions,particularly Ca2+,facilitated the binding of ssRNA to phospholipids due to their higher binding energy and lower dissociation rate from phospholipids.Overall,our study provides valuable insights into the molecular mechanisms underlying nucleic acidphospholipid interactions,with potential implications for the nucleic acids in biotherapies,particularly in the context of lipid carriers.展开更多
The current Chemistry at Harvard Molecular Mechanics (CHARMM) force field cannot accurately describe the properties of unsaturated phospholipid membranes. In this paper, a series of simulations was performed in which ...The current Chemistry at Harvard Molecular Mechanics (CHARMM) force field cannot accurately describe the properties of unsaturated phospholipid membranes. In this paper, a series of simulations was performed in which the Lennard- Jones (L-J) parameters of lipid acyl chains of dioleoylphosphatidylcholine (DOPC) were systematically adjusted. The results showed that adjustment of the L-J parameters in lipid acyl chains can significantly improve the current CHARMM force field. It was found that the L-J parameters have different influences on the order parameters of the top half and bottom half of the chain, separated by the cis double bond. The order parameters of the top half and the bottom half of the chain are related to the area/lipid and the length of the chain, respectively.展开更多
Molecular dynamics simulations have been performed on the fully hydrated lipid bilayer with different concentrations of sodium dodecyl sulfate (SDS). SDS can readily penetrate into the membrane. The insertion of SDS...Molecular dynamics simulations have been performed on the fully hydrated lipid bilayer with different concentrations of sodium dodecyl sulfate (SDS). SDS can readily penetrate into the membrane. The insertion of SDS causes a decrease in the bilayer area and increases in the bilayer thickness and lipid tail order, when the fraction of SDS is less than 28%. Through calculating the binding energy, we confirm that the presence of SDS strengthens the interactions among the DPPC lipids, while SDS molecules act as intermedia. Both the strong hydrophilic interactions between sulfate and phosphocholine groups and the hydrophobic interactions between SDS and DPPC hydrocarbon chains contribute to the tight packing and ordered alignment of the lipids. These results are in good agreement with the experimental observations and provide atomic level information that complements the experiments.展开更多
Spectrin, the principal protein of the cytoskeleton of erythrocyte, plays a crucial role in the stability and flexibility of the plasma membrane of erythrocyte. In this work, we investigate the interactions between sp...Spectrin, the principal protein of the cytoskeleton of erythrocyte, plays a crucial role in the stability and flexibility of the plasma membrane of erythrocyte. In this work, we investigate the interactions between spectrins and phase-separated lipid bilayers using coarse-grained molecular dynamics simulation. We focus on the preference of spectrins with different lipids, the effects of the anionic lipids and the residue mutation on the interactions between spectrins and the lipid bilayers. The results indicate that spectrins prefer to contact with phosphatidylethanolamine(PE) lipids rather than with phosphatidylcholine(PC) lipids, and tend to contact with the liquid-disordered(Ld) domains enriched in unsaturated PE.Additionally, the anionic lipids, which show specific interaction with the positively charged or polar amino acids on the surface of the spectrins, can enhance the attraction between the spectrins and lipid domains. The mutation leads to the decrease of the structural stability of spectrins and increases the curvature of the lipid bilayer. This work provides some theoretical insights into understanding the erythrocyte structure and the mechanism of some blood diseases.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
Soluble peptides or proteins can self-aggregate into insoluble, ordered amyloid fibrils under appropriate conditions. These amyloid aggregates are the hallmarks of several human diseases ranging from neurodegenerative...Soluble peptides or proteins can self-aggregate into insoluble, ordered amyloid fibrils under appropriate conditions. These amyloid aggregates are the hallmarks of several human diseases ranging from neurodegenerative disorders to sys- temic amyloidoses. In this review, we first introduce the common structural features of amyloid fibrils and the amyloid fibrillation kinetics determined from experimental studies. Then, we discuss the structural models of Alzheimer's amyloid- β (Aβ) fibrils derived from solid-state nuclear magnetic resonance spectroscopy. On the computational side, molecular dynamics simulations can provide atomic details of structures and the underlying oligomerization mechanisms. We finally summarize recent progress in atomistic simulation studies on the oligomerization of β (including full-length Af and its fragments) and the influence of carbon nanoparticles.展开更多
Because of the many potential medical applications of nanoparticles, considerable research has been conducted on the interactions between nanoparticles and biomembranes. We employed coarse- grained molecular dynamics ...Because of the many potential medical applications of nanoparticles, considerable research has been conducted on the interactions between nanoparticles and biomembranes. We employed coarse- grained molecular dynamics simulations to study the infiltration of lipid-wrapping C60 and polyhy- droxylated single-walled nanotubes. Diffusion coefficients and scaling factors are adopted to quantify the diffusivity of the biomembranes, and the rupture tension is used to measure the lateral strength of the lipid bilayer. According to our simulations, all wrapped nanoparticles, except those wrapped by dipalmitoyl-glycero-phosphoglycerol, can be inserted into the bilayers. Our simulations also re- veal that the bilayers remain in free diffusion after the nanoparticle insertions while their diffusion coefficient can be altered significantly. The polyhydroxylated single-walled nanotubes lead to signif- icant changes to the lateral strength of biomembranes and this effect depends on the quantity of the inserted nanoparticles. The simulations demonstrate the feasibility of using these methods to deliver nanopartieles while some suggestions are given for choosing the appropriate lipids for wrappiug. The results also suggest that the functionalized nanopartieles could be applied in strengthening or weakening the lateral strength of biomembranes for specific purposes.展开更多
Gramicidin A(gA)is a kind of antibiotic peptide produced by bacillus brevis and it can dimerize across lipid bilayers to form a monovalent cation channel.In this work,we investigate the impact of cholesterol in the li...Gramicidin A(gA)is a kind of antibiotic peptide produced by bacillus brevis and it can dimerize across lipid bilayers to form a monovalent cation channel.In this work,we investigate the impact of cholesterol in the lipid bilayer on the binding of potassium ions with the gA channel and the transport of the ions across the channel.The results indicate that cholesterol can significantly influence the conformational stability of the gA channel and cause the channel deformation which inhibits the potassium ion binding with the channel and transport across the channel.The work provides some molecular insights into understanding of influence of lipids on the activity of gA channel in both model membranes and plasma membranes of intact cells.展开更多
In this work, the previously developed coarse-grained (CG) particle models for biomembranes and red blood cells (RBCs) are reviewed, and the advantages of the CG particle methods over the continuum and atomistic s...In this work, the previously developed coarse-grained (CG) particle models for biomembranes and red blood cells (RBCs) are reviewed, and the advantages of the CG particle methods over the continuum and atomistic simulations for modeling biological phenomena are discussed. CG particle models can largely increase the length scale and time scale of atomistic simulations by eliminating the fast degrees of freedom while preserving the mesoscopic structures and properties of the simulated system. Moreover, CG particle models can be used to capture the microstructural alternations in diseased RBCs and simulate the topological changes of biomembranes and RBCs, which are the major challenges to the typical continuum representations of membranes and RBCs. The power and versatility of CG particle methods are demonstrated:through simulating the dynamical processes mvolving significant topological .changes e.g. lipid self-assembly vesicle fusion and membrane budding.展开更多
基金Project supported by the National Natural Science Foundation of China(Grant Nos.12222506,12347102,and 12174184).
文摘Recently,lipid nanoparticles(LNPs)have been extensively investigated as non-viral carriers of nucleic acid vaccines due to their high transport efficiency,safety,and straightforward production and scalability.However,the molecular mechanism underlying the interactions between nucleic acids and phospholipid bilayers within LNPs remains elusive.In this study,we employed the all-atom molecular dynamics simulation to investigate the interactions between single-stranded nucleic acids and a phospholipid bilayer.Our findings revealed that hydrophilic bases,specifically G in single-stranded RNA(ssRNA)and single-stranded DNA(ssDNA),displayed a higher propensity to form hydrogen bonds with phospholipid head groups.Notably,ssRNA exhibited stronger binding energy than ssDNA.Furthermore,divalent ions,particularly Ca2+,facilitated the binding of ssRNA to phospholipids due to their higher binding energy and lower dissociation rate from phospholipids.Overall,our study provides valuable insights into the molecular mechanisms underlying nucleic acidphospholipid interactions,with potential implications for the nucleic acids in biotherapies,particularly in the context of lipid carriers.
文摘The current Chemistry at Harvard Molecular Mechanics (CHARMM) force field cannot accurately describe the properties of unsaturated phospholipid membranes. In this paper, a series of simulations was performed in which the Lennard- Jones (L-J) parameters of lipid acyl chains of dioleoylphosphatidylcholine (DOPC) were systematically adjusted. The results showed that adjustment of the L-J parameters in lipid acyl chains can significantly improve the current CHARMM force field. It was found that the L-J parameters have different influences on the order parameters of the top half and bottom half of the chain, separated by the cis double bond. The order parameters of the top half and the bottom half of the chain are related to the area/lipid and the length of the chain, respectively.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.61575178 and 11574272)Zhejiang Provincial Natural Science Foundation of China(Grant No.LY16A040014)the Scientific Research and Developed Fund of Zhejiang A&F University,China(Grant No.2015FR022)
文摘Molecular dynamics simulations have been performed on the fully hydrated lipid bilayer with different concentrations of sodium dodecyl sulfate (SDS). SDS can readily penetrate into the membrane. The insertion of SDS causes a decrease in the bilayer area and increases in the bilayer thickness and lipid tail order, when the fraction of SDS is less than 28%. Through calculating the binding energy, we confirm that the presence of SDS strengthens the interactions among the DPPC lipids, while SDS molecules act as intermedia. Both the strong hydrophilic interactions between sulfate and phosphocholine groups and the hydrophobic interactions between SDS and DPPC hydrocarbon chains contribute to the tight packing and ordered alignment of the lipids. These results are in good agreement with the experimental observations and provide atomic level information that complements the experiments.
基金supported by the National Natural Science Foundation of China (Grant No. 11674287)Zhejiang Provincial Natural Science Foundation of China(Grant No. LY19A040009)。
文摘Spectrin, the principal protein of the cytoskeleton of erythrocyte, plays a crucial role in the stability and flexibility of the plasma membrane of erythrocyte. In this work, we investigate the interactions between spectrins and phase-separated lipid bilayers using coarse-grained molecular dynamics simulation. We focus on the preference of spectrins with different lipids, the effects of the anionic lipids and the residue mutation on the interactions between spectrins and the lipid bilayers. The results indicate that spectrins prefer to contact with phosphatidylethanolamine(PE) lipids rather than with phosphatidylcholine(PC) lipids, and tend to contact with the liquid-disordered(Ld) domains enriched in unsaturated PE.Additionally, the anionic lipids, which show specific interaction with the positively charged or polar amino acids on the surface of the spectrins, can enhance the attraction between the spectrins and lipid domains. The mutation leads to the decrease of the structural stability of spectrins and increases the curvature of the lipid bilayer. This work provides some theoretical insights into understanding the erythrocyte structure and the mechanism of some blood diseases.
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.
基金supported by the National Natural Science Foundation of China(Grant Nos.11274075 and 91227102)
文摘Soluble peptides or proteins can self-aggregate into insoluble, ordered amyloid fibrils under appropriate conditions. These amyloid aggregates are the hallmarks of several human diseases ranging from neurodegenerative disorders to sys- temic amyloidoses. In this review, we first introduce the common structural features of amyloid fibrils and the amyloid fibrillation kinetics determined from experimental studies. Then, we discuss the structural models of Alzheimer's amyloid- β (Aβ) fibrils derived from solid-state nuclear magnetic resonance spectroscopy. On the computational side, molecular dynamics simulations can provide atomic details of structures and the underlying oligomerization mechanisms. We finally summarize recent progress in atomistic simulation studies on the oligomerization of β (including full-length Af and its fragments) and the influence of carbon nanoparticles.
文摘Because of the many potential medical applications of nanoparticles, considerable research has been conducted on the interactions between nanoparticles and biomembranes. We employed coarse- grained molecular dynamics simulations to study the infiltration of lipid-wrapping C60 and polyhy- droxylated single-walled nanotubes. Diffusion coefficients and scaling factors are adopted to quantify the diffusivity of the biomembranes, and the rupture tension is used to measure the lateral strength of the lipid bilayer. According to our simulations, all wrapped nanoparticles, except those wrapped by dipalmitoyl-glycero-phosphoglycerol, can be inserted into the bilayers. Our simulations also re- veal that the bilayers remain in free diffusion after the nanoparticle insertions while their diffusion coefficient can be altered significantly. The polyhydroxylated single-walled nanotubes lead to signif- icant changes to the lateral strength of biomembranes and this effect depends on the quantity of the inserted nanoparticles. The simulations demonstrate the feasibility of using these methods to deliver nanopartieles while some suggestions are given for choosing the appropriate lipids for wrappiug. The results also suggest that the functionalized nanopartieles could be applied in strengthening or weakening the lateral strength of biomembranes for specific purposes.
基金Project supported by the National Natural Science Foundation of China(Grant No.11674287)the Zhejiang Provincial Natural Science Foundation of China(Grant No.LY19A040009)。
文摘Gramicidin A(gA)is a kind of antibiotic peptide produced by bacillus brevis and it can dimerize across lipid bilayers to form a monovalent cation channel.In this work,we investigate the impact of cholesterol in the lipid bilayer on the binding of potassium ions with the gA channel and the transport of the ions across the channel.The results indicate that cholesterol can significantly influence the conformational stability of the gA channel and cause the channel deformation which inhibits the potassium ion binding with the channel and transport across the channel.The work provides some molecular insights into understanding of influence of lipids on the activity of gA channel in both model membranes and plasma membranes of intact cells.
基金Project supported by the National Institutes of Health of U.S.A.(No.U01HL114476)the National Science Foundation of U.S.A.(Nos.CMMI-1235025 and PHY-1205910)
文摘In this work, the previously developed coarse-grained (CG) particle models for biomembranes and red blood cells (RBCs) are reviewed, and the advantages of the CG particle methods over the continuum and atomistic simulations for modeling biological phenomena are discussed. CG particle models can largely increase the length scale and time scale of atomistic simulations by eliminating the fast degrees of freedom while preserving the mesoscopic structures and properties of the simulated system. Moreover, CG particle models can be used to capture the microstructural alternations in diseased RBCs and simulate the topological changes of biomembranes and RBCs, which are the major challenges to the typical continuum representations of membranes and RBCs. The power and versatility of CG particle methods are demonstrated:through simulating the dynamical processes mvolving significant topological .changes e.g. lipid self-assembly vesicle fusion and membrane budding.
基金The project was supported by the National Natural Science Foundation of China(21422208)the Special Program for Applied Research on Super Computation of the Applied Research on Super Computation of the NSFC-Guangdong Joint Fund(U1501501)~~