Classical Models of Hydroxide for Proton Hopping Simulations.

Hydronium (HO) and hydroxide (OH) ions perform structural diffusion in water via sequential proton transfers ("Grotthuss hopping"). This phenomenon can be accounted for by interspersing stochastic proton transfer events in classical molecular dynamics simulations. The implementation of OH-mediated proton hopping is particularly challenging because classical force fields are known to produce overcoordinated solvation structures around the OH ion.

CHARMM at 45: Enhancements in Accessibility, Functionality, and Speed.

Since its inception nearly a half century ago, CHARMM has been playing a central role in computational biochemistry and biophysics. Commensurate with the developments in experimental research and advances in computer hardware, the range of methods and applicability of CHARMM have also grown. This review summarizes major developments that occurred after 2009 when the last review of CHARMM was published.

Scanning Small-/Wide-Angle X-ray Scattering for Polymer Electrolyte Fuel Cells: Investigation of Catalyst Layer Saturation and Membrane Hydration- Capabilities and Challenges.

Polymer electrolyte fuel cells are an essential technology for future local emission-free mobility. One of the critical challenges for thriving commercialization is water management in the cells. We propose small- and wide-angle X-ray scattering as a suitable diagnostic tool to quantify the liquid saturation in the catalyst layer and determine the hydration of the ion-conducting membrane in real operating conditions.

Transmembrane β-Barrel Models of α-Synuclein Oligomers.

The aggregation of α-synuclein is implicated in a number of neurodegenerative diseases, such as Parkinson's and Multiple System Atrophy, but the role of these aggregates in disease development is not clear. One possible mechanism of cytotoxicity is the disturbance or permeabilization of cell membranes by certain types of oligomers. However, no high-resolution structure of such membrane-embedded complexes has ever been determined.

Comparison of classical and ab initio simulations of hydronium and aqueous proton transfer.

Proton transport in aqueous systems occurs by making and breaking covalent bonds, a process that classical force fields cannot reproduce. Various attempts have been made to remedy this deficiency, by valence bond theory or instantaneous proton transfers, but the ability of such methods to provide a realistic picture of this fundamental process has not been fully evaluated. Here we compare an ab initio molecular dynamics (AIMD) simulation of an excess proton in water to a simulation of a classical H3O+ in TIP3P water.

Simulations suggest a scaffolding mechanism of membrane deformation by the caveolin 8S complex.

Caveolins form complexes of various sizes that deform membranes into polyhedral shapes. However, the recent structure of the 8S complex was disk-like with a flat membrane-binding surface. How can a flat complex deform membranes into nonplanar structures? Molecular dynamics simulations revealed that the 8S complex rapidly takes the form of a suction cup.

Proton Paths in Models of the Hv1 Proton Channel.

The voltage-gated proton channel (Hv1) plays an essential role in numerous biological processes, but a detailed molecular understanding of its function is lacking. The lack of reliable structures for the open and resting states is a major handicap. Several models have been built based on homologous voltage sensors and the structure of a chimera between the mouse homologue and a phosphatase voltage sensor, but their validity is uncertain.

Putative Pore Structures of Amyloid β 25-35 in Lipid Bilayers.

The amyloid β peptide aggregates to form extracellular plaques in the brains of Alzheimer's disease patients. Certain of its fragments have been found to have similar properties to those of the full-length peptide. The best-studied of these is 25-35, which aggregates into fibrils, is toxic to neurons, and forms ion channels in synthetic lipid bilayers.

Three-dimensional nanoimaging of fuel cell catalyst layers.

Catalyst layers in proton exchange membrane fuel cells consist of platinum-group-metal nanocatalysts supported on carbon aggregates, forming a porous structure through which an ionomer network percolates. The local structural character of these heterogeneous assemblies is directly linked to the mass-transport resistances and subsequent cell performance losses; its three-dimensional visualization is therefore of interest. Herein we implement deep-learning-aided cryogenic transmission electron tomography for image restoration, and we quantitatively investigate the full morphology of various catalyst layers at the local-reaction-site scale.

Putative Structures of Membrane-Embedded Amyloid β Oligomers.

Perturbation of cell membranes by amyloid β (Ab) peptide oligomers is one possible mechanism of cytotoxicity in Alzheimer's disease, but the structure of such Ab-membrane complexes is unknown. Here we examine the stability of several putative structures by implicit membrane and all-atom molecular dynamics simulations. The structures include (a) a variety of models proposed by other researchers in the past, (b) a heptameric β barrel determined by grafting the Ab sequence onto α-hemolysin, (c) a similar structure with modified strand orientation and turn location based on an experimental β-hairpin structure, (d) oligomers inserting C-terminal β hairpins into one leaflet of the bilayer, (e) oligomers forming parallel C-terminal β barrels, and (f) a helical hexamer made of C-terminal fragments.

Molecular origins of asymmetric proton conduction in the influenza M2 channel.

The M2 proton channel of influenza A is embedded into the viral envelope and allows acidification of the virion when the external pH is lowered. In contrast, no outward proton conductance is observed when the internal pH is lowered, although outward current is observed at positive voltage. Residues Trp41 and Asp44 are known to play a role in preventing pH-driven outward conductance, but the mechanism for this is unclear.

Amino acid deprotonation rates from classical force fields.

Acid ionization constants (pK's) of titratable amino acid side chains have received a large amount of experimental and theoretical attention. In many situations, however, the rates of protonation and deprotonation, k and k, may also be important, for example, in understanding the mechanism of action of proton channels or membrane proteins that couple proton transport to other processes. Protonation and deprotonation involve the making and breaking of covalent bonds, which cannot be studied by classical force fields.

Mechanism of negative membrane curvature generation by I-BAR domains.

The membrane sculpting ability of BAR domains has been attributed to the intrinsic curvature of their banana-shaped dimeric structure. However, there is often a mismatch between this intrinsic curvature and the diameter of the membrane tubules generated. I-BAR domains are especially mysterious since they are almost flat but generate high negative membrane curvature.

Distinct Modes of Action of IAPP Oligomers on Membranes.

Islet amyloid polypeptide (IAPP, also known as amylin) is a peptide hormone that is co-secreted with insulin by pancreatic β-cells and forms amyloid aggregates in type II diabetes. Various lines of evidence indicate that oligomers of this peptide may induce toxicity by disrupting or forming pores in cell membranes, but the structure of these pores is unknown. Here, we create models of pores for both helical and β-structured peptides using implicit membrane modeling and test their stability using multimicrosecond all-atom simulations.

Lipid interactions of an actinoporin pore-forming oligomer.

The actinoporins are cytolytic toxins produced by sea anemones. Upon encountering a membrane, preferably containing sphingomyelin, they oligomerize and insert their N-terminal helix into the membrane, forming a pore. Whether sphingomyelin is specifically recognized by the protein or simply induces phase coexistence in the membrane has been debated.

Free energy of hydrophilic and hydrophobic pores in lipid bilayers by free energy perturbation of a restraint.

The free energy of pore formation in lipid bilayers has been previously calculated using a variety of reaction coordinates. Here, we use free energy perturbation of a cylindrical lipid exclusion restraint to compute the free energy profile as a function of pore radius in dimyristoylphosphatidylcholine (DMPC) and dioleoylphosphatidylcholine (DOPC) bilayers. Additionally restraining the headgroups to lie on the membrane surface allows us to also calculate the free energy profile of hydrophobic pores, i.

The value of antimicrobial peptides in the age of resistance.

Accelerating growth and global expansion of antimicrobial resistance has deepened the need for discovery of novel antimicrobial agents. Antimicrobial peptides have clear advantages over conventional antibiotics which include slower emergence of resistance, broad-spectrum antibiofilm activity, and the ability to favourably modulate the host immune response. Broad bacterial susceptibility to antimicrobial peptides offers an additional tool to expand knowledge about the evolution of antimicrobial resistance.

Correction to: Experimental and Computational Characterization of Oxidized and Reduced Protegrin Pores in Lipid Bilayers.

The original version of the article was published without the Graphic Abstract. Graphic Abstract image of the article is given below.

Experimental and Computational Characterization of Oxidized and Reduced Protegrin Pores in Lipid Bilayers.

Protegrin-1 (PG-1), an 18-residue β-hairpin stabilized by two disulfide bonds, is a member of a family of powerful antimicrobial peptides which are believed to act through membrane permeabilization. Here we used a combination of experimental and computational approaches to characterize possible structural arrangements of PG-1 in lipid bilayers mimicking bacterial membranes. We have measured the dose-response function of the PG-1-induced leakage of markers of various sizes from vesicles and found it to be consistent with the formation of pores of two different sizes.

What Makes a Good Pore Former: A Study of Synthetic Melittin Derivatives.

Pore formation by membrane-active peptides, naturally encountered in innate immunity and infection, could have important medical and technological applications. Recently, the well-studied lytic peptide melittin has formed the basis for the development of combinatorial libraries from which potent pore-forming peptides have been derived, optimized to work under different conditions. We investigate three such peptides, macrolittin70, which is most active at neutral pH; pHD15, which is active only at low pH; and MelP5_Δ6, which was rationally designed to be active at low pH but formed only small pores.

Mechanisms of negative membrane curvature sensing and generation by ESCRT III subunit Snf7.

Certain proteins have the propensity to bind to negatively curved membranes and generate negative membrane curvature. The mechanism of action of these proteins is much less studied and understood than those that sense and generate positive curvature. In this work, we use implicit membrane modeling to explore the mechanism of an important negative curvature sensing and generating protein: the main ESCRT III subunit Snf7.

Effects of Peptide Charge, Orientation, and Concentration on Melittin Transmembrane Pores.

Melittin is a short cationic peptide that exerts cytolytic effects on bacterial and eukaryotic cells. Experiments suggest that in zwitterionic membranes, melittin forms transmembrane toroidal pores supported by four to eight peptides. A recently constructed melittin variant with a reduced cationic charge, MelP5, is active at 10-fold lower concentrations.

Membrane Curvature Sensing by Amphipathic Helices: Insights from Implicit Membrane Modeling.

Sensing and generation of lipid membrane curvature, mediated by the binding of specific proteins onto the membrane surface, play crucial roles in cell biology. A number of mechanisms have been proposed, but the molecular understanding of these processes is incomplete. All-atom molecular dynamics simulations have offered valuable insights but are extremely demanding computationally.

Classical Molecular Dynamics with Mobile Protons.

An important limitation of standard classical molecular dynamics simulations is the inability to make or break chemical bonds. This restricts severely our ability to study processes that involve even the simplest of chemical reactions, the transfer of a proton. Existing approaches for allowing proton transfer in the context of classical mechanics are rather cumbersome and have not achieved widespread use and routine status.

Transmembrane Pore Structures of β-Hairpin Antimicrobial Peptides by All-Atom Simulations.

Protegrin-1 is an 18-residue β-hairpin antimicrobial peptide (AMP) that has been suggested to form transmembrane β-barrels in biological membranes. However, alternative structures have also been proposed. Here, we performed multimicrosecond, all-atom molecular dynamics simulations of various protegrin-1 oligomers on the membrane surface and in transmembrane topologies.