Coarse-Grained Force Field for Polyethylene Oxide and Polyethylene Glycol Aqueous Solutions Based on a Polarizable Water Model.

A new, accurate and transferable coarse-grained (CG) force field (FF) for polyethylene oxide (PEO) and polyethylene glycol (PEG) aqueous solutions based on a polarizable CG water (PCGW) model is developed in this work. A PCGW bead, which represents four water molecules, is modeled as two charged dummy particles connected by two constrained bonds to a central neutral particle; a PEO or PEG oligomer is modeled as a chain with repeated middle beads (PEOM) representing diether groups and two terminal beads (PEOT or PEGT) of a different type compared to PEOM. To describe nonbonded van der Waals interactions, a piecewise Morse potential with four tunable parameters is used. The force parameters are automatically and rigorously optimized by a meta-multilinear interpolation parameterization (meta-MIP) algorithm to simultaneously match multiple thermodynamic properties, including the density, heat of vaporization, vapor-liquid interfacial tension, and solvation free energy of the pure PEO or PEG oligomer bulk system as well as the mixing density and hydration free energy of the oligomer/water binary mixture. Additional thermodynamic and structural properties for longer PEO and PEG polymer aqueous solutions, such as the self-diffusion coefficient, radius of gyration, and end-to-end distance, are predicted to test the accuracy and transferability of this new CG FF. Based on the PCGW model, the presented FF optimization algorithm and strategy can be extended to more complex polyelectrolytes and surfactants.

A top-down and bottom-up combined strategy for parameterization of coarse-grained force fields for phospholipids.

Coarse-graining (CG) molecular dynamics (MD) simulations are widely used in interpreting experimental observations and predicting assembly morphology as well as collective behaviour but also face the problem of poor accuracy. A main issue is that cross-termed interactions between different CG beads are inadequately parameterized. This work proposes a novel top-down and bottom-up combined strategy to parameterize both self- and cross-termed interactions of zwitterionic phospholipids in water solution based on a piecewise Morse potential describing nonbonded van der Waals interactions. The self-interacting force parameters were optimized by matching experimental density, heat vapourization, and surface tension in a top-down manner, while the cross-termed interactions were optimized by fitting pseudo properties obtained from atomistic simulations in a bottom-up way, including mixing density, intermolecular energy, and radial mixing coefficient. The transferability of the CG force field (FF) was confirmed by reproducing a variety of structural and thermodynamic properties of lipid membranes in both liquid and gel phases. This FF can well depict vesicle self-assembly and vesicle fusion processes. Matching pseudo properties opens a new way to develop CG FF with increased accuracy and transferability.

Development of accurate coarse-grained force fields for weakly polar groups by an indirect parameterization strategy.

Coarse-grained (CG) molecular dynamics simulations are widely used to predict morphological structures and interpret mechanisms of mesoscopic behavior between the scope of traditional experiments and all-atom simulations. However, most current CG force fields (FFs) are not precise enough, especially for polar molecules or functional groups. A main obstacle in developing accurate CG FFs for polar molecules is the freezing problem met at room temperature. In this work, we introduce an indirect parametrization strategy for weakly polar groups by considering their short-chain homologs to avoid freezing. Here, a polar group containing three to four heavy atoms is mapped into one CG bead that is connected to one alkyl bead composed of three or four carbons. The CG beads interact via 4-parameter nonbonded Morse potentials and harmonic bonded potentials. An efficient meta-multilinear interpolation parameterization algorithm, as recently developed by us, is used to rigorously optimize the force parameters. Satisfactory accuracy is witnessed in terms of the density, heat of vaporization, surface tension, and solvation free energy of the homologs of twelve polar molecules, all deviating from the experiment by less than 5%. The transferability of the current FF is indicated by the predicted density, heat of vaporization, and end-to-end distance distributions of fatty acid methyl esters composed of multiple functional groups parameterized in this work.

Development of coarse-grained force field for alcohols: an efficient meta-multilinear interpolation parameterization algorithm.

Coarse-grained (CG) molecular dynamics are powerful tools to access a mesoscopic phenomenon and simultaneously record microscopic details, but currently the CG force fields (FFs) are still limited by low parameterization efficiency and poor accuracy especially for polar molecules. In this work, we developed a Meta-Multilinear Interpolation Parameterization (Meta-MIP) algorithm to optimize the CG FFs for alcohols. This algorithm significantly boosts parameterization efficiency by constructing on-the-fly local databases to cover the global optimal parameterization path. In specific, an alcohol molecule is mapped to a heterologous model composed of an OH bead and a hydrocarbon portion which consists of alkane beads representing two to four carbon atoms. Non-bonded potentials are described by soft Morse functions that have no tail-corrections but can still retain good continuities at truncation distance. Nearly all of the properties in terms of density, heat of vaporization, surface tension, and solvation free energy for alcohols predicted by the current FFs deviate from experimental values by less than 7%. This Meta-MIP algorithm can be readily applied to force field development for a wide variety of molecules or functional groups, in many situations including but not limited to CG FFs.

Polymyxin B Loosens Lipopolysaccharide Bilayer but Stiffens Phospholipid Bilayer.

Multidrug-resistant Gram-negative bacteria have increased the prevalence of a variety of serious diseases in modern times. Polymyxins are used as the last-line therapeutic options for the treatment of infections. However, the mechanism of action of polymyxins remains in dispute. In this work, we used a coarse-grained molecular dynamics simulation to investigate the mechanism of the cationic antimicrobial peptide polymyxin B (PmB) interacting with both the inner and outer membrane models of bacteria. Our results show that the binding of PmB disturbs the outer membrane by displacing the counterions, decreasing the orientation order of the lipopolysaccharide tail, and creating more lipopolysaccharide packing defects. Upon binding onto the inner membrane, in contrast to the traditional killing mechanism that antimicrobial peptides usually use to induce holes in the membrane, PmBs do not permeabilize the inner membrane but stiffen it by filling up the lipid packing defect, increasing the lipid tail order and the membrane bending rigidity as well as restricting the lipid diffusion. PmBs also mediate intermembrane contact and adhesion. These joint effects suggest that PmBs deprive the biological activity of Gram-negative bacteria by sterilizing the cell.

Development of Coarse-Grained Force Field by Combining Multilinear Interpolation Technique and Simplex Algorithm.

A fast, reasonable, and transferable coarse-grained (CG) molecular dynamics force field (FF) is essential to combine experimental and simulation data. However, the parameterization of CG FF usually requires massive computation, which hinders its rapid development. Here, we presented an efficient optimization protocol by combining multilinear interpolation technique with simplex algorithm. In this preliminary work, taking the experimental properties as the benchmark, we constructed a new set of CG FF for water and n-alkanes by adopting piecewise Morse function to describe the nonbonded interactions. This CG FF has a delicate balance between efficiency, accuracy, and transferability and well reproduced the correct structural and thermodynamics properties of pure water and alkane liquids. More importantly, optimized Morse potential was also successfully applied to describe the interactions between water and n-alkanes. It nicely predicted the phase separation, interface tension, hydration free energy, and formation of microemulsions of water/oil mixtures. © 2019 Wiley Periodicals, Inc.

Peripheral Antimicrobial Peptide Gomesin Induces Membrane Protrusion, Folding, and Laceration.

Optical microscopy shows that the peripheral antimicrobial peptide (AMP) gomesin does not disrupt the bacterial membrane by forming stable transmembrane pores but induces lipid accumulation domains, which is followed by a sudden burst near the domains. The molecular action mechanisms of gomesin on vesicle and planar bilayer membranes are investigated in this work using coarse-grained molecular dynamics simulations. By comparing the membrane morphology and property changes induced by gomesin and the pore-forming AMP melittin, we determined that the amphiphilic shape of the AMPs is a key factor affecting the mechanism of cell death. The binding of wedge-shaped gomesin, with a small hydrophobic surface, onto the membrane induces protrusion and folding of the outer monolayer followed by sudden membrane lacerations at the axillae of the protuberances. Alternatively, cylinder-shaped melittins with comparable hydrophilic and hydrophobic surfaces destroy membranes by forming stable pores coexisting with exocytosis-like buddings and endocytosis-like invaginations. The multiple actions of AMPs on the bacterial membrane suggest diverse paradigms for designing molecular carriers for delivering drugs to the cell.

Peptide-Lipid Interaction Sites Affect Vesicles' Responses to Antimicrobial Peptides.

This article presents coarse-grained molecular dynamics simulations of pore-forming antimicrobial peptide melittin and its interactions with vesicles composed of a mixture of zwitterionic and anionic phospholipids. Besides creating holes in the membrane, the adsorption of melittin also induces vesicle budding, which can develop into vesiculation at high peptide concentrations, as well as vesicle invagination, which can eventually result in a corrugated membrane surface. These rich morphology changes are mediated by the curvature of the vesicles and the peptide concentration. Highly curved vesicles favor the recruitment of melittins with a higher density of binding sites. The peptides mainly penetrate into the membrane surface in monomers via hydrophobic interaction. Lowly curved vesicles recruit melittins with a low density of binding sites. Surplus peptides are prone to form oligomers and shallowly adsorb on the surface of membrane via electrostatic interaction. The penetration of monomers induces membrane pore formation and positive membrane curvature, which promote vesicle budding. The adsorption of oligomers induces negative membrane curvature, which promotes vesicle invagination. This work demonstrates that antimicrobial peptides adopt multiple actions to destroy bacterial membranes.

Implicit-solvent dissipative particle dynamics force field based on a four-to-one coarse-grained mapping scheme.

A new set of efficient solvent-free dissipative particle dynamics (DPD) force fields was developed for phospholipids and peptides. To enhance transferability, this model maps around four heavy atoms and their connected hydrogen atoms into a coarse-grained elementary bead based on functional group. The effective hybrid potential between any pair of beads is composed of a short-range repulsive soft-core potential that directly adopts the form of an explicit-solvent DPD model and a long-range attractive hydrophobic potential. The parameters of the attractive potentials for lipid molecules were obtained by fitting the explicit-solvent DPD simulation of one bead of any type in a water box, then finely tuning it until the bilayer membrane properties obtained in the explicit-solvent model were matched. These parameters were further extended to amino acids according to bead type. The structural and elastic properties of bilayer membranes, free energy profiles for a lipid flip-flop and amino acid analogues translocating across the membrane, and membrane pore formation induced by antimicrobial peptides obtained from this solvent-free DPD force field considerably agreed with the explicit-solvent DPD results. Importantly, the efficiency of this method is guaranteed to accelerate the assembly of vesicles composed of several thousand lipids by up to 50-fold, rendering the experimental liposome dynamics as well as membrane-peptide interactions feasible at accessible computational expense.

Formation Mechanism and Properties of Polyelectrolyte Multilayer-Supported Lipid Bilayers: A Coarse-Grained Molecular Dynamics Study.

Polyelectrolyte multilayer (PEM)-supported lipid bilayers (SLBs) that connect with functional proteins are popular models for cell membranes and are usually obtained via vesicle adsorption and spreading. However, the exact mechanism by which SLBs are formed is not fully understood. In this study, we employ coarse-grained molecular dynamics simulations to investigate the pathways by which vesicles undergo spreading upon the deposition on PEM-cushioned substrates. The substrates consist of positive chitosan (CHI)/negative alginate (ALG) multilayers. We find that an isolated vesicle tends to completely disintegrate upon deposition, forming a well-ordered lipid bilayer at appropriate polymer ionic strengths by a mechanism described as "parachute" model. Lipids from the vesicle's outer leaflet are predominantly oriented toward the bulk after the formation of the SLB. The PEM cushion provides adsorption energy of 26.9 kJ mol-1 per lipid for the SLBs. The process by which SLBs are formed is almost independent of the number of layers of CHI/ALG in the PEM cushion. Additional simulations on vesicle clusters also demonstrate that the formation of SLBs can be catalyzed by either neighboring vesicles or preexisting bilayer edges on the support. Moreover, our simulations show that SLBs created on PEM supports preserve the lateral mobility and the symmetric density profile of the phospholipids, as in a freestanding bilayer.

Polyelectrolyte multilayer-cushioned fluid lipid bilayers: a parachute model.

Lipid bilayer membranes supported on polyelectrolyte multilayers are widely used as a new biomembrane model that connects biological and artificial materials since these ultrathin polyelectrolyte supports may mimic the role of the extracellular matrix and cell skeleton in living systems. Polyelectrolyte multilayers were fabricated by a layer-by-layer self-assembly technique. A quartz crystal microbalance with dissipation was used in real time to monitor the interaction between phospholipids and polyelectrolytes in situ on a planar substrate. The surface properties of polyelectrolyte films were investigated by the measurement of contact angles and zeta potential. Phospholipid charge, buffer pH and substrate hydrophilicity were proved to be essential for vesicle adsorption, rupture, fusion and formation of continuous lipid bilayers on the polyelectrolyte multilayers. The results clearly demonstrated that only the mixture of phosphatidylcholine and phosphatidic acid (4 : 1) resulted in fluid bilayers on chitosan and alginate multilayers with chitosan as a top layer at pH 6.5. A coarse-grained molecular simulation study elucidated that the exact mechanism of the formation of fluid lipid bilayers resembles a "parachute" model. As the closest model to the real membrane, polyelectrolyte multilayer-cushioned fluid lipid bilayers can be appropriate candidates for application in biomedical fields.

Self-assembly of gold nanorods coated with phospholipids: a coarse-grained molecular dynamics study.

The self-assembly of phospholipid-coated gold nanorods (GNRs) was investigated by coarse-grained molecular dynamics simulations. We predict that in addition to the formation of deformed vesicles encapsulating GNRs with diverse orientations, the lipid-coated GNRs can form a semi-ring attached to an excess vesicle phase, a branch with excess vesicle phase, a ring phase, a branch phase, a stack phase, and a vortex phase. The morphologies of the lipid-GNR complexes depend on the lipid/GNR molar ratio and the interaction strength between the nanorod surface and the lipid head groups. At given lipid-nanorod interactions, removing the lipid induces a phase transition from an isolated ring or branch phase to an aggregated vortex or stack phase and vice versa. As the lipid-coated GNRs transit from an isolated phase to an aggregated phase, the structure of the lipid at the nanorod surface converts from a bilayer state to a non-bilayer state.

Mechanism of Inhibition of Human Islet Amyloid Polypeptide-Induced Membrane Damage by a Small Organic Fluorogen.

Human islet amyloid polypeptide (hIAPP) is believed to be responsible for the death of insulin-producing ß-cells. However, the mechanism of membrane damage at the molecular level has not been fully elucidated. In this article, we employ coarse- grained dissipative particle dynamics simulations to study the interactions between a lipid bilayer membrane composed of 70% zwitterionic lipids and 30% anionic lipids and hIAPPs with α-helical structures. We demonstrated that the key factor controlling pore formation is the combination of peptide charge-induced electroporation and peptide hydrophobicity-induced lipid disordering and membrane thinning. According to these mechanisms, we suggest that a water-miscible tetraphenylethene BSPOTPE is a potent inhibitor to rescue hIAPP-induced cytotoxicity. Our simulations predict that BSPOTPE molecules can bind directly to the helical regions of hIAPP and form oligomers with separated hydrophobic cores and hydrophilic shells. The micelle-like hIAPP-BSPOTPE clusters tend to be retained in the water/membrane interface and aggregate therein rather than penetrate into the membrane. Electrostatic attraction between BSPOTPE and hIAPP also reduces the extent of hIAPP binding to the anionic lipid bilayer. These two modes work together and efficiently prevent membrane poration.