Pulling out a peptide chain from β-sheet crystallite: Propagation of instability of H-bonds under shear force

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.

Mechanics of water pore formation in lipid membrane under electric field

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.

Interactions of human islet amyloid polypeptide with lipid structure of different curvatures

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.

Quantification of the stiffness and strength of cadherin ectodomain binding with different ions

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.

Protein conformational transitions coupling with ligand interactions:Simulations from molecules to medicine

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.

An atomistic model of silk protein network for studying the effect of pre-stretching on the mechanical performances of silks

Silk protein builds one of the strongest natural fibers based on its complex nanocomposite structures.However,the mechanical performance of silk protein,related to its molecular structure and packing is still elusive.In this study,we constructed an atomistic silk protein network model,which reproduces the extensive connection topology of silk protein with structure details of theβ-sheet crystallites and amorphous domains.With the silk protein network model,we investigated the structure evolution and stress distribution of silk protein under external loading.We found a pre-stretching treatment during the spinning process can improve the strength of silk protein.This treatment improves the properties of silk protein network,i.e.,increases the number of nodes and bridges,makes the nodes distributed homogeneously,and induces the bridges in the network well aligned to the loading direction,which is of great benefit to the mechanical performances of silk protein.Our study not only provides a realized atomistic model for silk protein network that well represents the structures and deformations of silk proteins under loading,but also gains deep insights into the mechanism how the pre-loading on silk proteins during spinning improves the mechanical properties of silk fibers.

Heterogeneous oxidization of graphene nanosheets damages membrane

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.

Single-vesicle imaging quantifies calcium’s regulation of nanoscale vesicle clustering mediated by α-synuclein

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.