Xiaozheng Duan

Monte Carlo Study of Polyelectrolyte Adsorption on Mixed Lipid Membrane

Monte Carlo simulations are employed to investigate the adsorption of a flexible linear cationic polyelectrolyte onto a fluid mixed membrane containing neutral (phosphatidyl-choline, PC), multivalent (phosphatidylinositol, PIP(2)), and monovalent (phosphatidylserine, PS) anionic lipids. We systematically study the effect of chain length and charge density of the polyelectrolyte, the solution ionic strength, as well as the membrane compositions on the conformational and interfacial properties of the model system. In particular, we explore (i) the adsorption/desorption limit, (ii) the interfacial structure variations of the adsorbing polyelectrolyte and the lipid membrane, and (iii) the overcharging of the membrane. Polyelectrolyte adsorbs on the membrane when anionic lipid demixing entropy loss and polyelectrolyte flexibility loss due to adsorption are dominated by electrostatic attraction between polyelectrolyte and anionic lipids on the membrane. Polyelectrolytes with longer chain length and higher charge density can adsorb on the membrane with increased anionic lipid density under a higher critical ionic concentration. Below the critical ionic concentration, the adsorption extent increases with the charge density and chain length of the polyelectrolyte and decreases with the ionic strength of the solution. The diffusing anionic lipids prohibit the polyelectrolyte chain from forming too long tails. The adsorbing polyelectrolyte with long chain length and high charge density can overcharge a membrane with low charge density, and conversely, the membrane charge inversion forces the polyelectrolyte chain to form extended loops and tails in the solution.

Regulation of anionic lipids in binary membrane upon the adsorption of polyelectrolyte: A Monte Carlo simulation

We employ Monte Carlo simulations to investigate the interaction between an adsorbing linear flexible cationic polyelectrolyte and a binary fluid membrane. The membrane contains neutral phosphatidyl–choline, PC) and multivalent anionic (phosphatidylinositol, PIP2) lipids. We systematically study the influences of the solution ionic strength, the chain length and the bead charge density of the polyelectrolyte on the lateral rearrangement and the restricted mobility of the multivalent anionic lipids in the membrane. Our findings show that, the cooperativity effect and the electrostatic interaction of the polyelectrolyte beads can significantly affect the segregation extent and the concentration gradients of the PIP2 molecules, and further cooperate to induce the complicated hierarchical mobility behaviors of PIP2 molecules. In addition, when the polyelectrolyte brings a large amount of charges, it can form a robust electrostatic well to trap all PIP2 and results in local overcharge of the membrane. This wor...

Compositional redistribution and dynamic heterogeneity in mixed lipid membrane induced by polyelectrolyte adsorption: Effects of chain rigidity

Monte Carlo simulation is employed to investigate the interaction between a polyelectrolyte and a fluid mixed membrane containing neutral (phosphatidyl-choline, PC), monovalent anionic (phosphatidylserine, PS), and multivalent anionic (phosphatidylinositol, PIP2) lipids. The effects of the intrinsic polyelectrolyte rigidity and solution ionic strength on the lateral rearrangement and dynamics of different anionic lipid species are systematically studied. Our results show that, the increase of polyelectrolyte chain rigidity reduces the loss of polyelectrolyte conformational entropy and the energy gains in electrostatic interaction, but raises the demixing entropy loss of the segregated anionic lipids. Therefore, the polyelectrolyte/membrane adsorption strength exhibits a non-monotonic dependence on the polyelectrolyte rigid parameter kang, and there exists a certain optimal kang for which the adsorption strength is maximal. Because the less loss of chain conformational entropy dominates the increase of the demixing entropy loss of the segregated anionic lipids and the decreases of the electrostatic energy gains, the semiflexible polyelectrolyte adsorbs onto the membrane more firmly than the flexible one. Whereas, for the adsorption of rigid polyelectrolyte, larger anionic lipid demixing entropy loss and less energy gain in the electrostatic interaction dominate over the decrease of the polyelectrolyte conformation entropy loss, leading to the desorption of the chain from the membrane. By decreasing the ionic concentration of the salt solution, the certain optimal kang shifts to larger values. The cooperative effects of the adsorbing polyelectrolyte beads determine the concentration gradients and hierarchical mobility of the bound anionic lipids, as well as the polyelectrolyte dynamics.Graphical abstract

Effect of polyelectrolyte adsorption on lateral distribution and dynamics of anionic lipids: a Monte Carlo study of a coarse-grain model

We employ Monte Carlo simulations to investigate the interaction between an adsorbing linear flexible cationic polyelectrolyte and a ternary mixed fluid membrane containing neutral (phosphatidylcholine, PC), monovalent (phosphatidylserine, PS), and multivalent (phosphatidylinositol, PIP2) anionic lipids. We systematically explore the influences of polyelectrolyte chain length, polyelectrolyte charge density, polyelectrolyte total charge amount, and salt solution ionic strength on the static and dynamic properties of different anionic lipid species. Our results show that the multivalent PIP2 lipids dominate the polyelectrolyte–membrane interaction and competitively inhibit polyelectrolyte–PS binding. When the total charge amount of the polyelectrolyte is less than that of the local oppositely charged PIP2 lipids, the polyelectrolyte can drag the bound multivalent lipids to diffuse on the membrane, but cannot interact with the PS lipids. Under this condition, the diffusion behaviors of the polyelectrolyte closely follow the prediction of the Rouse model, and the polyelectrolyte chain properties determine the adsorption amount, concentration gradients, and hierarchical mobility of the bound PIP2 lipids. However, when the total charge amount of the polyelectrolyte is larger than that of the local PIP2 lipids, the polyelectrolyte further binds the PS lipids around the polyelectrolyte–PIP2 complex to achieve local electrical neutrality. In this condition, parts of the polyelectrolyte desorb from the membrane and show faster mobility, and the bound PS presents much faster mobility than the segregated PIP2. This work provides an explanation for heterogeneity formation in different anionic lipids induced by polyelectrolyte adsorption.

Flow-induced polymer translocation through a nanopore from a confining nanotube

We study the flow-induced polymer translocation through a nanopore from a confining nanotube, using a hybrid simulation method that couples point particles into a fluctuating lattice-Boltzmann fluid. Our simulation illustrates that the critical velocity flux of the polymer linearly decreases with the decrease in the size of the confining nanotube, which corresponds well with our theoretical analysis based on the blob model of the polymer translocation. Moreover, by decreasing the size of the confining nanotube, we find a significantly favorable capture of the polymer near its ends, as well as a longer translocation time. Our results provide the computational and theoretical support for the development of nanotechnologies based on the ultrafiltration and the single-molecule sequencing.

Spatial Rearrangement and Mobility Heterogeneity of an Anionic Lipid Monolayer Induced by the Anchoring of Cationic Semiflexible Polymer Chains

We use Monte Carlo simulations to investigate the interactions between cationic semiflexible polymer chains and a model fluid lipid monolayer composed of charge-neutral phosphatidyl-choline (PC), tetravalent anionic phosphatidylinositol 4,5-bisphosphate (PIP2), and univalent anionic phosphatidylserine (PS) lipids. In particular, we explore how chain rigidity and polymer concentration influence the spatial rearrangement and mobility heterogeneity of the monolayer under the conditions where the cationic polymers anchor on the monolayer. We find that the anchored cationic polymers only sequester the tetravalent PIP2 lipids at low polymer concentrations, where the interaction strength between the polymers and the monolayer exhibits a non-monotonic dependence on the degree of chain rigidity. Specifically, maximal anchoring occurs at low polymer concentrations, when the polymer chains have an intermediate degree of rigidity, for which the PIP2 clustering becomes most enhanced and the mobility of the polymer/PIP2 complexes becomes most reduced. On the other hand, at sufficiently high polymer concentrations, the anchoring strength decreases monotonically as the chains stiffen—a result that arises from the pronounced competitions among polymer chains. In this case, the flexible polymers can confine all PIP2 lipids and further sequester the univalent PS lipids, whereas the stiffer polymers tend to partially dissociate from the monolayer and only sequester smaller PIP2 clusters with greater mobilities. We further illustrate that the mobility gradient of the single PIP2 lipids in the sequestered clusters is sensitively modulated by the cooperative effects between anchored segments of the polymers with different rigidities. Our work thus demonstrates that the rigidity and concentration of anchored polymers are both important parameters for tuning the regulation of anionic lipids.

Effects of Concentration and Ionization Degree of Anchoring Cationic Polymers on the Lateral Heterogeneity of Anionic Lipid Monolayers

We employed coarse-grained Monte Carlo simulations to investigate a system composed of cationic polymers and a phosphatidyl-choline membrane monolayer, doped with univalent anionic phosphatidylserine (PS) and tetravalent anionic phosphatidylinositol 4,5-bisphosphate (PIP2) lipid molecules. For this system, we consider the conditions under which multiple cationic polymers can anchor onto the monolayer and explore how the concentration and ionization degree of the polymers affect the lateral rearrangement and fluidity of the negatively charged lipids. Our work shows that the anchoring cationic polymers predominantly bind the tetravalent anionic PIP2 lipids and drag the PIP2 clusters to migrate on the monolayer. The polymer/PIP2 binding is found to be drastically enhanced by increasing the polymer ionization fraction, which causes the PIP2 lipids to form into larger clusters and reduces the mobility of the polymer/PIP2 complexes. As expected, stronger competition effects between anchoring polymers occur at higher polymer concentrations, for which each anchoring polymer partially dissociates from the monolayer and hence sequesters a smaller PIP2 cluster. The desorbed segments of the anchored polymers exhibit a faster mobility on the membrane, whereas the PIP2 clusters are closely restrained by the limited adhering cationic segments of anchoring polymers. We further demonstrate that the PIP2 molecules display a hierarchical mobility in the PIP2 clusters, which is regulated by the synergistic effect between the cationic segments of the polymers. The PS lipids sequester in the vicinity of the polymer/PIP2 complexes if the tetravalent PIP2 lipids cannot sufficiently neutralize the cationic polymers. Finally, we illustrate that the increase in the ionic concentration of the solution weakens the lateral clustering and the mobility heterogeneity of the charged lipids. Our work thus provides a better understanding of the fundamental biophysical mechanism of the concentration gradients and the hierarchical mobility of the anionic lipids in the membrane caused by the cationic polymer anchoring on length and time scales that are generally inaccessible by atomistic models. It also offers insight into the development and design of novel biological applications on the basis of the modulation of signaling lipids.

Molecular Dynamics Simulation of Salt Diffusion in Polyelectrolyte Assemblies

The diffusion of salt ions and charged probe molecules in polyelectrolyte (PE) assemblies is often assumed to follow a theoretical hopping model, in which the diffusing ion hops between charged sites of chains based on electroneutrality. However, experimental verification of diffusing pathway at such microscales is difficult, and the corresponding molecular mechanisms remain elusive. In this study, we perform all-atom molecular dynamics simulations of salt diffusion in the PE assembly of poly(sodium-4-styrenesulfonate) (PSS) and poly(diallyldimethylammonium chloride) (PDAC). Besides the ion hopping mode, the diffusing trajectories are found to present common features of a jump process, that is, subjecting to PE relaxation, water pockets in the structure open and close; thus, the ion can move from one pocket to another. Anomalous subdiffusion of ions and water is observed because of the trapping scenarios in these water pockets. The jump events are much rarer compared with ion hopping but significantly increases salt diffusion with increasing temperature. Our result strongly indicates that salt diffusion in hydrated PDAC/PSS is a combined process of ion hopping and jump motion. This provides a new molecular explanation for the coupling of salt motion with chain motion and the nonlinear increase of salt diffusion at glass-transition temperature.

Mutation Induced Structural Variation in Membrane Proteins

Point mutations on membrane proteins may lead to small structural variations. Prediction of such structural variations can help to further understand the related bio-activities of membrane proteins. We constructed fifteen hybrid energy functions on the basis of Chemistry at Harvard Macromolecular Mechanics(CHARMM) force field, hydrogen bonding potential and distance-scaled, finite ideal-gas reference(DFIRE)-like statistical energies, and evaluated their performance on a representative dataset of homologous membrane proteins via a newly developed all-atom replica exchange Monte Carlo algorithm. The energy function composed of CHARMM and hydrogen bonding potential has the best performance, and the original DFIRE potential shows much better performance than the DFIRE-like potentials constructed from membrane proteins. We can conclude that more membrane protein structures with high resolution are necessary for the construction of robust prediction method of mutation induced membrane protein structure variations.