Anti-parallel β-sheet crystallite as the main component of silk fibroin has attracted much attention due to its superior mechanical properties. In this study, we examine the processes of pulling a peptide chain from ...Anti-parallel β-sheet crystallite as the main component of silk fibroin has attracted much attention due to its superior mechanical properties. In this study, we examine the processes of pulling a peptide chain from β-sheet crystallite using steered molecular dynamics simulations to investigate the rupture behavior of the crystallite. We show that the failure of β-sheet crystallite was accompanied by a propagation of instability of hydrogen-bonds (H-bonds) in the crystallite. In addition, we find that there is an optimum size of the crystallite at which the H-bonds can work cooperatively to achieve the highest shear strength. In addition, we find that the stiffness of loading device and the loading rates have significant effects on the rupture behavior of β-sheet crystallite. The stiff loading device facilitates the rebinding of the Hbond network in the stick-slip motion between the chains, while the soft one suppresses it. Moreover, the rupture force of β-sheet crystallites decreases with loading rate. Particularly, when the loading rate decreases to a critical value, the rupture force of the β-sheet crystallite becomes independent of the loading rates. This study provides atomistic details of rupture behaviors of β-sheet crystallite, and, therefore, sheds valuable light on the underlying mechanism of the superior mechanical properties of silk fibroin.展开更多
Transmembrane water pores are crucial for substance transport through cell membranes via membrane fusion, such as in neural communication. However, the molecular mechanism of water pore formation is not clear. In this...Transmembrane water pores are crucial for substance transport through cell membranes via membrane fusion, such as in neural communication. However, the molecular mechanism of water pore formation is not clear. In this study, we apply all-atom molecular dynamics and bias-exchange metadynamics simulations to study the process of water pore formation under an electric field. We show that water molecules can enter a membrane under an electric field and form a water pore of a few nanometers in diameter. These water molecules disturb the interactions between lipid head groups and the ordered arrangement of lipids. Following the movement of water molecules, the lipid head groups are rotated and driven into the hydrophobic region of the membrane. The reorientated lipid head groups inside the membrane form a hydrophilic surface of the water pore. This study reveals the atomic details of how an electric field influences the movement of water molecules and lipid head groups, resulting in water pore formation.展开更多
Curvature is one of the most important features of lipid membranes in living cells,which significantly influences the structure of lipid membranes and their interaction with proteins.Taken the human islet amyloid poly...Curvature is one of the most important features of lipid membranes in living cells,which significantly influences the structure of lipid membranes and their interaction with proteins.Taken the human islet amyloid polypeptide(h IAPP),an important protein related to the pathogenesis of type II diabetes,as an example,we performed molecular dynamics(MD)simulations to study the interaction between the protein and the lipid structures with varied curvatures.We found that the lipids in the high curvature membrane pack loosely with high mobility.The h IAPP initially forms H-bonds with the membrane surface that anchored the protein,and then inserts into the membrane through the hydrophobic interactions between the residues and the hydrophobic tails of the lipids.h IAPP can insert into the membrane more deeply with a larger curvature and with a stronger binding strength.Our result provided important insights into the mechanism of the membrane curvature-dependent property of proteins with molecular details.展开更多
The stiffness and strength of extracellular (EC) region of cadherin are proposed to be two important mechanical properties both for cadherin as a mechanotransductor and for the formation of cell-cell adhesion. In th...The stiffness and strength of extracellular (EC) region of cadherin are proposed to be two important mechanical properties both for cadherin as a mechanotransductor and for the formation of cell-cell adhesion. In this study, we quantitatively characterized the stiffness and strength of EC structure when it binds with different types of ions by molecular dynamics simulations. Resuits show that EC structure exhibits a rod-like shape with high stiffness and strength when it binds with the bivalent ions of calcium or magnesium. However, it switches to a soft and collapsed conformation when it binds with the monova- lent ions of sodium or potassium. This study sheds light on the important role of the bivalent ions of calcium in the physiological function of EC.展开更多
The functions and activities of proteins are closely related to their structures and dynamics,and their interactions with ligands.Knowledge of the mechanistic events of proteins’conformational transitions and interac...The functions and activities of proteins are closely related to their structures and dynamics,and their interactions with ligands.Knowledge of the mechanistic events of proteins’conformational transitions and interactions with ligands is crucially important to understand the functions and biological activities of proteins and thus to the design of novel inhibitors of the targeted receptor.In this review article,taking two important systems as examples,i.e.,human immunodeficiency virus type 1 protease(HIV-1 PR)and adenylate kinase(AdK),and focusing on the molecular dynamics simulations of the conformational transitions of protein and the protein-ligand association/dissociation,we explain how the conformational transitions of proteins influence the interactions with their ligands,and how the ligands impact the function and dynamics of proteins.These results of structural dynamics of HIV-1 PR and AdK and their interactions with ligands can help to understand the principle of conformational transitions of proteins,or the interactions of ligands to their biological targets,and thus provide meaningful message in chemistry and biology of drug design and discovery.展开更多
Graphene-based materials exhibit unique properties that have been sought to utilize for various potential applications. Many studies suggest that graphene-based materials can be cytotoxic, which may be attributed to d...Graphene-based materials exhibit unique properties that have been sought to utilize for various potential applications. Many studies suggest that graphene-based materials can be cytotoxic, which may be attributed to destructive effects on cell membranes.However, there still are conflicting results regarding interactions between graphene-based materials and lipid membranes. Here,through cryo-electron microscopy(Cryo-EM) and dye-leakage experiments along with in silico methods, we found that graphene oxide nanosheets induce significant membrane damage, while the effect of pristine graphene is negligible. We revealed the importance of heterogeneous oxidization of graphene-based nanosheets in damaging vesicle membranes. Moreover, that not only the oxidization degree but also the oxidization loci and membrane tension play important roles in the cytotoxicity of the graphene-based nanosheets.展开更多
Although numerous studies have shown that the proteinα-synuclein(α-Syn)plays a central role in Parkinson’s disease,dementia with Lewy bodies,and other neurodegenerative diseases,the protein’s physiological functio...Although numerous studies have shown that the proteinα-synuclein(α-Syn)plays a central role in Parkinson’s disease,dementia with Lewy bodies,and other neurodegenerative diseases,the protein’s physiological function remains poorly understood.Furthermore,despite recent reports suggesting that,under the influence of Ca^(2+),α-Syn can interact with synaptic vesicles,the mechanisms underlying that interaction are far from clear.Thus,we used single-vesicle imaging to quantify the extent to which Ca^(2+)regulates nanoscale vesicle clustering mediated by α-Syn.Our results revealed not only that vesicle clustering requiredα-Syn to bind to anionic lipid vesicles,but also that different concentrations of Ca^(2+)exerted different effects on howα-Syn induced vesicle clustering.In particular,low concentrations of Ca^(2+)inhibited vesicle clustering by blocking the electrostatic interaction between the lipid membrane and the N terminus of α-Syn,whereas high concentrations promoted vesicle clustering,possibly due to the electrostatic interaction between Ca^(2+)and the negatively charged lipids that is independent of α-Syn.Taken together,our results provide critical insights intoα-Syn’s physiological function,and how Ca^(2+) regulates vesicle clustering mediated by α-Syn.展开更多
基金supported by the National Science Foundation of China (Grants 11025208, 11372042, 11221202, and 11202026)the support from CSIRO-Intelligent Processing TCP+1 种基金CAFHS’ Capability Development FundCSIRO-Advanced Materials TCP
文摘Anti-parallel β-sheet crystallite as the main component of silk fibroin has attracted much attention due to its superior mechanical properties. In this study, we examine the processes of pulling a peptide chain from β-sheet crystallite using steered molecular dynamics simulations to investigate the rupture behavior of the crystallite. We show that the failure of β-sheet crystallite was accompanied by a propagation of instability of hydrogen-bonds (H-bonds) in the crystallite. In addition, we find that there is an optimum size of the crystallite at which the H-bonds can work cooperatively to achieve the highest shear strength. In addition, we find that the stiffness of loading device and the loading rates have significant effects on the rupture behavior of β-sheet crystallite. The stiff loading device facilitates the rebinding of the Hbond network in the stick-slip motion between the chains, while the soft one suppresses it. Moreover, the rupture force of β-sheet crystallites decreases with loading rate. Particularly, when the loading rate decreases to a critical value, the rupture force of the β-sheet crystallite becomes independent of the loading rates. This study provides atomistic details of rupture behaviors of β-sheet crystallite, and, therefore, sheds valuable light on the underlying mechanism of the superior mechanical properties of silk fibroin.
基金supported by the National Natural Science Foundation of China (Grants 11372042, 11221202, 11532009, and 11202026)
文摘Transmembrane water pores are crucial for substance transport through cell membranes via membrane fusion, such as in neural communication. However, the molecular mechanism of water pore formation is not clear. In this study, we apply all-atom molecular dynamics and bias-exchange metadynamics simulations to study the process of water pore formation under an electric field. We show that water molecules can enter a membrane under an electric field and form a water pore of a few nanometers in diameter. These water molecules disturb the interactions between lipid head groups and the ordered arrangement of lipids. Following the movement of water molecules, the lipid head groups are rotated and driven into the hydrophobic region of the membrane. The reorientated lipid head groups inside the membrane form a hydrophilic surface of the water pore. This study reveals the atomic details of how an electric field influences the movement of water molecules and lipid head groups, resulting in water pore formation.
基金supported by funds from the National Natural Science Foundation of China(Grants 11932017,11772054,11772055,and 11532009)supported by the Fundamental Research Funds for the Central Universities(Grant 2019QNA4060)。
文摘Curvature is one of the most important features of lipid membranes in living cells,which significantly influences the structure of lipid membranes and their interaction with proteins.Taken the human islet amyloid polypeptide(h IAPP),an important protein related to the pathogenesis of type II diabetes,as an example,we performed molecular dynamics(MD)simulations to study the interaction between the protein and the lipid structures with varied curvatures.We found that the lipids in the high curvature membrane pack loosely with high mobility.The h IAPP initially forms H-bonds with the membrane surface that anchored the protein,and then inserts into the membrane through the hydrophobic interactions between the residues and the hydrophobic tails of the lipids.h IAPP can insert into the membrane more deeply with a larger curvature and with a stronger binding strength.Our result provided important insights into the mechanism of the membrane curvature-dependent property of proteins with molecular details.
基金supported by the National Natural Science Foundation of China(11025208,11221202,11372042,and 11202026)the Excellent Young Scholars Research Fund of Beijing Institute of Technology
文摘The stiffness and strength of extracellular (EC) region of cadherin are proposed to be two important mechanical properties both for cadherin as a mechanotransductor and for the formation of cell-cell adhesion. In this study, we quantitatively characterized the stiffness and strength of EC structure when it binds with different types of ions by molecular dynamics simulations. Resuits show that EC structure exhibits a rod-like shape with high stiffness and strength when it binds with the bivalent ions of calcium or magnesium. However, it switches to a soft and collapsed conformation when it binds with the monova- lent ions of sodium or potassium. This study sheds light on the important role of the bivalent ions of calcium in the physiological function of EC.
基金supported by the Natural Science Foundation of China(Grants No.11932017,11772055,11772054,11221202,11202026,and 11532009)the Fundamental Research Funds for the Central Universities(Grant No.2019QNA4060).
文摘The functions and activities of proteins are closely related to their structures and dynamics,and their interactions with ligands.Knowledge of the mechanistic events of proteins’conformational transitions and interactions with ligands is crucially important to understand the functions and biological activities of proteins and thus to the design of novel inhibitors of the targeted receptor.In this review article,taking two important systems as examples,i.e.,human immunodeficiency virus type 1 protease(HIV-1 PR)and adenylate kinase(AdK),and focusing on the molecular dynamics simulations of the conformational transitions of protein and the protein-ligand association/dissociation,we explain how the conformational transitions of proteins influence the interactions with their ligands,and how the ligands impact the function and dynamics of proteins.These results of structural dynamics of HIV-1 PR and AdK and their interactions with ligands can help to understand the principle of conformational transitions of proteins,or the interactions of ligands to their biological targets,and thus provide meaningful message in chemistry and biology of drug design and discovery.
基金supported by the National Basic Research Program of China(Grant No.2015CB856304)the National Natural Science Foundation of China(Grant Nos.11772054,11772055,11532009,and 11402145)+1 种基金Natural Science Foundation of Shanghai(Grant No.18ZR1418800)National Institutes of Health(Grant No.R35GM128837)
文摘Graphene-based materials exhibit unique properties that have been sought to utilize for various potential applications. Many studies suggest that graphene-based materials can be cytotoxic, which may be attributed to destructive effects on cell membranes.However, there still are conflicting results regarding interactions between graphene-based materials and lipid membranes. Here,through cryo-electron microscopy(Cryo-EM) and dye-leakage experiments along with in silico methods, we found that graphene oxide nanosheets induce significant membrane damage, while the effect of pristine graphene is negligible. We revealed the importance of heterogeneous oxidization of graphene-based nanosheets in damaging vesicle membranes. Moreover, that not only the oxidization degree but also the oxidization loci and membrane tension play important roles in the cytotoxicity of the graphene-based nanosheets.
基金We thank Dr.Chirlmin Joo for help in preparing the figure of the TIRFM setup and Dr.Tom Thompson for help with the CD experiments.B.B.,D.L.,L.Z.,W.D.,and B.J.were supported by funds from the National Natural Science Foundation of China(NSFC 11932017,11772054,11772055,11532009,11902051,and 31871031)W.D.was supported by the Sichuan Science and Technology Program(2019YJ0481)+1 种基金D.L.was supported by the Fundamental Research Funds for the Central Universities(Grant no.2019QNA4060)J.D.was supported by the Michael J Fox Foundation(ID 16661).
文摘Although numerous studies have shown that the proteinα-synuclein(α-Syn)plays a central role in Parkinson’s disease,dementia with Lewy bodies,and other neurodegenerative diseases,the protein’s physiological function remains poorly understood.Furthermore,despite recent reports suggesting that,under the influence of Ca^(2+),α-Syn can interact with synaptic vesicles,the mechanisms underlying that interaction are far from clear.Thus,we used single-vesicle imaging to quantify the extent to which Ca^(2+)regulates nanoscale vesicle clustering mediated by α-Syn.Our results revealed not only that vesicle clustering requiredα-Syn to bind to anionic lipid vesicles,but also that different concentrations of Ca^(2+)exerted different effects on howα-Syn induced vesicle clustering.In particular,low concentrations of Ca^(2+)inhibited vesicle clustering by blocking the electrostatic interaction between the lipid membrane and the N terminus of α-Syn,whereas high concentrations promoted vesicle clustering,possibly due to the electrostatic interaction between Ca^(2+)and the negatively charged lipids that is independent of α-Syn.Taken together,our results provide critical insights intoα-Syn’s physiological function,and how Ca^(2+) regulates vesicle clustering mediated by α-Syn.