Recalibration of MARTINI-3 Parameters for Improved Interactions between Peripheral Proteins and Lipid Bilayers.

The MARTINI force field is one of the most used coarse-grained models for biomolecular simulations. Many limitations of the model including the protein-protein overaggregation have been improved in its latest version, MARTINI-3. In this study, we investigate the efficacy of the MARTINI-3 parameters for capturing the interactions of peripheral proteins with model plasma membranes.

Dynamins combine mechano-constriction and membrane remodeling to enable two-step mitochondrial fission via a 'snap-through' instability.

Mitochondrial fission is controlled by dynamin proteins, the dysregulation of which is correlated with diverse diseases. Fission dynamins are GTP hydrolysis-driven mechanoenzymes that self-oligomerize into helical structures that constrict membrane to achieve fission, but details are not well understood. However, dynamins can also remodel membranes by inducing negative Gaussian curvature, the type of curvature required for completion of fission.

SARS-CoV-2 spike fusion peptide interaction with phosphatidylserine lipid triggers membrane fusion for viral entry.

Unlabelled: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike is the fusion machine for host cell entry. Still, the mechanism by which spike protein interacts with the target lipid membrane to facilitate membrane fusion during entry is not fully understood. Here, using steady-state membrane fusion and single-molecule fluorescence resonance energy transfer imaging of spike trimers on the surface of SARS-CoV-2 pseudovirion, we directly show that spike protein interacts with phosphatidylserine (PS) lipid in the target membrane for mediating fusion.

Comparing Multifunctional Viral and Eukaryotic Proteins for Generating Scission Necks in Membranes.

Deterministic formation of membrane scission necks by protein machinery with multiplexed functions is critical in biology. A microbial example is M2 viroporin, a proton pump from the influenza A virus that is multiplexed with membrane remodeling activity to induce budding and scission in the host membrane during viral maturation. In comparison, the dynamin family constitutes a class of eukaryotic proteins implicated in mitochondrial fission, as well as various budding and endocytosis pathways.

Comparing multifunctional viral and eukaryotic proteins for generating scission necks in membranes.

Deterministic formation of membrane scission necks by protein machinery with multiplexed functions is critical in biology. A microbial example is the M2 viroporin, a proton pump from the influenza A virus which is multiplexed with membrane remodeling activity to induce budding and scission in the host membrane during viral maturation. In comparison, the dynamin family constitutes a class of eukaryotic proteins implicated in mitochondrial fission, as well as various budding and endocytosis pathways.

Synaptotagmin-7 outperforms synaptotagmin-1 to promote the formation of large, stable fusion pores via robust membrane penetration.

Synaptotagmin-1 and synaptotagmin-7 are two prominent calcium sensors that regulate exocytosis in neuronal and neuroendocrine cells. Upon binding calcium, both proteins partially penetrate lipid bilayers that bear anionic phospholipids, but the specific underlying mechanisms that enable them to trigger exocytosis remain controversial. Here, we examine the biophysical properties of these two synaptotagmin isoforms and compare their interactions with phospholipid membranes.

How Cell-Penetrating Peptides Behave Differently from Pore-Forming Peptides: Structure and Stability of Induced Transmembrane Pores.

Peptide-induced transmembrane pore formation is commonplace in biology. Examples of transmembrane pores include pores formed by antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs) in bacterial membranes and eukaryotic membranes, respectively. In general, however, transmembrane pore formation depends on peptide sequences, lipid compositions, and intensive thermodynamic variables and is difficult to observe directly under realistic solution conditions, with structures that are challenging to measure directly.

Origin of the nonlinear structural and mechanical properties in oppositely curved lipid mixtures.

Structural and mechanical properties of membranes such as thickness, tail order, bending modulus and curvature energetics play crucial role in controlling various cellular functions that depend on the local lipid organization and membrane reshaping. While behavior of these biophysical properties are well understood in single component membranes, very little is known about how do they change in the mixed lipid membranes. Often various properties of the mixed lipid bilayers are assumed to change linearly with the mole fractions of the constituent lipids which, however, is true for "ideal" mixing only.

Simulation study of membrane bending by protein crowding: a case study with the epsin N-terminal homology domain.

The mechanisms by which peripheral membrane proteins generate curvature is currently an active area of research. One of the proposed mechanisms is amphipathic insertion or the 'wedge' mechanism in which the protein shallowly inserts an amphipathic helix inside the membrane to drive the curvature. However, recent experimental studies have challenged the efficiency of the 'wedge' mechanism as it requires unusual protein densities.

Simulation study of domain formation in a model bacterial membrane.

Recent experimental studies revealed that functional membrane microdomains (FMMs) are formed in prokaryotic cells which are structurally and functionally similar to the lipid rafts formed in eukaryotic cells. In this study, we employ coarse-grained molecular dynamics simulations to investigate the mechanism of domain formation and its physiochemical properties in a model methicillin-resistant (MRSA) cell membrane. We find that domains are formed through lateral segregation of staphyloxanthin (STX), a carotenoid which shields the bacteria from the host's immune because of its antioxidant nature.

Scission energy and topology of micelles controlled by the molecular structure of additives.

We employ coarse-grained (CG) molecular dynamics simulations (MD) to investigate the effects of the molecular structure of additives on the scission energy and morphology of charged micelles. Considering sodium dodecyl sulfate (SDS) as a representative charged surfactant and taking trimethylphenylammonium chloride (TMPAC) and octyltrimethylammonium bromide (OTAB) as oppositely charged additives, we show that the scission energy and topology of micelles vary significantly depending on the molecular structure of the hydrophobic part of the additives. The cyclic aromatic tail of the TMPAC disrupts the core structure of the SDS micelle and hence decreases the micelle scission energy, whereas the linear alkyl tail of the OTAB packs very well with the micelle core and increases the scission energy.

The complexin C-terminal amphipathic helix stabilizes the fusion pore open state by sculpting membranes.

Neurotransmitter release is mediated by proteins that drive synaptic vesicle fusion with the presynaptic plasma membrane. While soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs) form the core of the fusion apparatus, additional proteins play key roles in the fusion pathway. Here, we report that the C-terminal amphipathic helix of the mammalian accessory protein, complexin (Cpx), exerts profound effects on membranes, including the formation of pores and the efficient budding and fission of vesicles.

Protein-induced membrane curvature in coarse-grained simulations.

Using the endosomal sorting complex required for transport (ESCRT)-III membrane remodeling complex as an example, we analyze three popular coarse-grained models (the regular MARTINI, polarizable MARTINI (POL-MARTINI), and big multipole water MARTINI (BMW-MARTINI)) for the description of membrane curvature sensing and generation activities of peripheral proteins. Although the three variants of the MARTINI model provide consistent descriptions for the protein-protein interface in a linear filament model of ESCRT-III, they differ considerably in terms of protein-membrane interface and therefore membrane curvature sensing and generation behaviors. In particular, BMW-MARTINI provides the most consistent description of the protein-membrane interface as compared to all-atom simulations, whereas the regular MARTINI is most consistent with atomistic simulations in terms of the qualitative sign of membrane curvature sensing and generation.

Cholesterol Interaction with the Trimeric HIV Fusion Protein gp41 in Lipid Bilayers Investigated by Solid-State NMR Spectroscopy and Molecular Dynamics Simulations.

HIV-1 entry into cells is mediated by the fusion protein gp41. Cholesterol plays an important role in this virus-cell fusion, but molecular structural information about cholesterol-gp41 interaction is so far absent. Here, we present experimental and computational data about cholesterol complexation with gp41 in lipid bilayers.

Modulating Interdendrimer Interactions through Surface Adsorption.

Physical confinement of polymers not only affects their structure but also modifies their effective interaction profiles. In this article, we investigate the nature of graphene-adsorbed poly(amidoamine) (PAMAM) dendrimers' interactions using fully atomistic molecular dynamics simulations. Using the umbrella sampling technique, we calculate the potential of mean force (PMF) profiles for the interaction between two graphene-adsorbed PAMAM dendrimers of generations 3 and 4 as a function of their protonation levels.

Photo-Disassembly of Membrane Microdomains Revives Conventional Antibiotics against MRSA.

Confronted with the rapid evolution and dissemination of antibiotic resistance, there is an urgent need to develop alternative treatment strategies for drug-resistant pathogens. Here, an unconventional approach is presented to restore the susceptibility of methicillin-resistant (MRSA) to a broad spectrum of conventional antibiotics via photo-disassembly of functional membrane microdomains. The photo-disassembly of microdomains is based on effective photolysis of staphyloxanthin, the golden carotenoid pigment that gives its name.

Molecular Simulation of Mechanical Properties and Membrane Activities of the ESCRT-III Complexes.

The endosomal sorting complex required for transport (ESCRT) machinery carries out the membrane scission reactions that are required for many biological processes throughout cells. How ESCRTs bind and deform cellular membranes and ultimately produce vesicles has been a matter of active research in recent years. In this study, we use fully atomistic molecular dynamics simulations to scrutinize the structural details of a filament composed of Vps32 protomers, a major component of ESCRT-III complexes.

Stretch and Breakage of Wormlike Micelles under Uniaxial Strain: A Simulation Study and Comparison with Experimental Results.

We use coarse-grained (CG) molecular dynamics simulations to determine the effect of uniaxial strain on the stress, scission stress, and scission energy of solutions of wormlike micelles of cetyltrimethylammonium chloride/sodium salicylate (NaSal). We find that the breaking stress, stretch modulus, and scission energy of the charged micelles are nonmonotonic functions of oppositely charged hydrotrope (NaSal) concentration. While the stretch modulus shows a peak at a value of surfactant-to-hydrotrope concentration ratio ( R) close to unity as expected due to neutralization of head-group charge at R = 1, the breaking stress and scission energy produce a peak at R < 1.

Nonmonotonic Scission and Branching Free Energies as Functions of Hydrotrope Concentration for Charged Micelles.

Using coarse-grained molecular dynamics simulations and an umbrella sampling method that uses local surfactant density as a reaction coordinate, we directly calculate, for the first time, both the scission and branching free energies of a model charged micelle [cationic cetyltrimethylammonium chloride (CTAC)] in the presence of inorganic and organic salts (hydrotropes). We find that while inorganic salt only weakly affects the micelle scission energy, organic hydrotropes produce a strong, nonmonotonic dependence of both scission energy and branching on salt concentration. The nonmonotonicity in scission energy is traced to a competition between electrostatic screening of the repulsions among the surfactant head groups and thinning of the micellar core, which result from attachment of the hydrotropes to the micelle surface.

Prediction of striped cylindrical micelles (SCMs) formed by dodecyl-β-d-maltoside (DDM) surfactants.

Using fully atomistic and coarse-grained (CG) molecular dynamics (MD) simulations, we report, for the first time, the self-assembly of initially randomly dispersed dodecyl-β-d-maltoside (DDM) surfactants into a striped cylindrical micelle (SCM) with lamellae of surfactant heads and tails alternating along the cylindrical axis, with both heads and tails in contact with the water. By changing the interaction strength of the head group with water relative to itself, we find that such micelles are most likely for head groups with marginal solubility in the water solvent. Unlike the surfactants in a regular cylindrical micelle, whose tails are in the fluid micelle interior, the diffusion of DDM surfactants along the micelle body is blocked by the lamellar patterning.

Translocation of Bioactive Molecules through Carbon Nanotubes Embedded in the Lipid Membrane.

One of the major challenges of nanomedicine and gene therapy is the effective translocation of drugs and genes across cell membranes. In this study, we describe a systematic procedure that could be useful for efficient drug and gene delivery into the cell. Using fully atomistic molecular dynamics (MD) simulations, we show that molecules of various shapes, sizes, and chemistries can be spontaneously encapsulated in a single-walled carbon nanotube (SWCNT) embedded in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer, as we have exemplified with dendrimers, asiRNA, ssDNA, and ubiquitin protein.

Multiscale Computational Modeling of the Nanostructure of Solid Dispersions of Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS) and Phenytoin.

We recently developed coarse-grained (CG) force fields for hydroxypropyl methylcellulose acetate succinate (HPMCAS) polymers and the model drug molecule phenytoin, and a continuum transport model to study the polymer-drug nanostructures presented during a dissolution test after solvation of solid dispersion particles. We model the polymer-drug interactions that contribute to suppression of drug aggregation, release, and crystal growth during the dissolution process, and we take these as indicators of polymer effectiveness. We find that the size and the intermolecular interaction strength of the functional group and the drug loading concentration are the major factors that impact the effectiveness of the polymeric excipient.

Nucleation of urea from aqueous solution: Structure, critical size, and rate.

Using fully atomistic simulations, we find that the structure of the critical urea crystal nucleus (monoclinic, four molecules per unit cell) in an aqueous solution differs from the known crystal structure of bulk urea (orthorhombic, two molecules per unit cell). Following a frequently used "seeding technique" combined with the classical nucleation theory, we also find that at room temperature the critical nucleus is very large (containing ∼530 molecules) and the nucleation rate is very slow (∼5×10cms), suggesting that the homogeneous nucleation of urea is improbable at room temperature.

A framework for multi-scale simulation of crystal growth in the presence of polymers.

We present a multi-scale simulation method for modeling crystal growth in the presence of polymer excipients. The method includes a coarse-grained (CG) model for small molecules of known crystal structure whose force field is obtained using structural properties from atomistic simulations. This CG model is capable of stabilizing the molecular crystal structure and capturing the crystal growth from the melt for a wide range of small organic molecules, as demonstrated by application of our method to the molecules isoniazid, urea, sulfamethoxazole, prilocaine, oxcarbazepine, and phenytoin.