Rong Wang

DNA-mediated membrane fusion has great prospects in spatiotemporal control over fusion events, attributed to DNA's inherent programmability and addressability. However, the kinetics remain largely unknown, and whether zipper-like hybridization orientation is a prerequisite remains an open question. Herein, we employed a coarse-grained molecular dynamics method to systematically investigate the mechanism and kinetics of DNA-mediated liposome fusion under two distinct DNA binding modes: zipper and bridge. The results indicated that zipper mode is more favorable for fusion, while bridge mode exhibits a strong dependence on DNA linker length. The free energy barriers of liposome fusion were determined to be 10.17 k_BT for zipper mode and 12.21 k_BT for bridge mode, respectively. Furthermore, the membrane curvature and surface DNA density were identified as the main factors affecting fusion kinetics, and the optimal parameter ranges for promoting liposome fusion were also determined. These findings provide valuable insights for the rational design and optimization of DNA-mediated liposome fusion systems.

The binding of membrane receptors to their ligands anchored in an apposing membrane mediates such biological processes as cell adhesion and signaling, and is known to be determined not only by direct receptor-ligand interactions but also by such factors as flexibility and thermal fluctuations of the apposing membranes. The binding of soluble ligands to membrane receptors initiates various cellular processes; however, to the best of our knowledge, its dependence on membrane properties has not been studied. Here, we employed molecular dynamics simulations to fill in this knowledge gap. Our simulations demonstrate that, in the absence of specific lipid-protein interactions and clustering of membrane receptors, the equilibrium and kinetic rate constants for the binding of soluble ligands to membrane receptors are determined almost entirely by direct receptor-ligand interactions and are practically unaffected by the curvature, flexibility and thermal fluctuations of the membrane.

Targeting vesicles can be designed via co-assembly of amphiphilic block copolymers and DNA ligands, with tunable ligand distribution on vesicle surfaces by adjusting interactions among DNA, hydrophilic blocks, and solvent.

Colloidal molecules, novel nanoparticle clusters with molecular-like structures, can enhance material performance and broaden applications in nanotechnology and materials science. However, constructing them with a precise, controllable architecture remains challenging. Inspired by the concepts of chemical reaction, we theoretically design a novel type of nanoparticles bifunctionalized by DNA strands and polymer chains and propose a stepwise strategy to hierarchically program the assembly of bifunctionalized nanoparticles into well-defined colloidal molecules by virtue of coarse-grained molecular dynamics simulations. This method leverages the synergistic effects of polymers and DNA to create programmable atom-like nanoparticles with various valence domains. By carefully designing strands, these nanoparticles are programmed to coassemble into various colloidal molecules with distinct symmetries and coordination numbers, which can be finely tuned by the molecular design of nanoparticles as well as the composition design of the coassembly system. Our strategy provides a novel protocol for the controlled coassembly of nanoparticles into customized colloidal molecules, expanding nanomaterial manufacturing techniques.

Adhesion of biological cells is essential for various processes, including tissue formation, immune responses, and signaling. It involves multiple length scales, ranging from nanometers to micrometers, which are characteristic of (a) the intercellular receptor-ligand binding that mediates the cell adhesion, (b) the spatial distribution of the receptor and ligand proteins in the membranes of adhering cells, (c) adhesion-induced deformations and thermal undulations of the membranes, (d) the overall size of the interface between adhering cells. Therefore, computer simulations of cell membrane adhesion require multiscale modeling and suitable approximations that capture the essential physics of the system under study. Here, we introduce such a multiscale approach to study membrane adhesion mediated by the CD47-SIRPα binding, which is an immunologically relevant process. The synergetic use of coarse-grained molecular dynamics simulations and mesoscale kinetic Monte Carlo simulations allows us to explore both equilibrium properties and dynamical behavior of adhering membranes on the relevant length scales between 1 nm and 1 μm on time scales ranging from 0.1 ns all the way up to about 20 s. The multiscale simulations not only reproduce available experimental data but also give quantitative predictions on binding-induced conformational changes of SIRPα and membrane-mediated cooperativity of the CD47-SIRPα binding as well as fluctuation-induced interactions between the CD47-SIRPα complexes. Our approach is applicable to various membrane proteins and provides invaluable data for comparison with experimental findings.

Polymeric vesicles present great potential in disease treatment as they can be featured as a structurally stable and easily functionalized drug carrier that can simultaneously encapsulate multiple drugs and release them on-demand. Based on the dissipative particle dynamics (DPD) simulation, the drug-loaded vesicles were designed by the co-assembly process of linear amphiphilic triblock copolymers and hydrophobic nanodrugs in solvents, and most importantly, the drug release behavior of drug-loaded vesicles were intensively investigated. The drug-loaded aggregates, such as vesicles, spherical micelles, and disk-like micelles, were observed by varying the size and concentration of nanodrugs and the length of the hydrophobic block. The distribution of nanodrugs in the vesicles was intensively analyzed. As the size of the nanodrugs increases, the localization of nanodrugs change from being unable to fully wrap in the vesicle wall to the uniform distribution and finally to the aggregation in the vesicles at the fixed concentration of nanodrugs. The membrane thickness of the drug-loaded polymeric vesicle can be increased, and the nanodrugs localized closer to the center of the vesicle by increasing the length of the hydrophobic block. The nanodrugs will be released from vesicles by varying the interactions between the nanodrug and the solvent or the hydrophobic block and the solvent, respectively. We found that the release kinetics conforms to the first-order kinetic model, which can be used to fit the cumulative release rate of nanodrugs over time. The results showed that increasing the size of nanodrugs, the length of hydrophobic block, and the interaction parameters between the hydrophobic block and the solvent will slow down the release rate of the nanodrug and change the drug release process from monophasic to biphasic release model.