The effect of membrane curvature on the conformation of antimicrobial peptides: implications for binding and the mechanism of action

Short cationic antimicrobial peptides (AMPs) are believed to act either by inducing transmembrane pores or disrupting membranes in a detergent-like manner. For example, the antimicrobial peptides aurein 1.2, citropin 1.1, maculatin 1.1 and caerin 1.1, despite being closely related, appear to act by fundamentally different mechanisms depending on their length. Using molecular dynamics simulations, the structural properties of these four peptides have been examined in solution as well as in a variety of membrane environments. It is shown that each of the peptides has a strong preference for binding to regions of high membrane curvature and that the structure of the peptides is dependent on the degree of local curvature. This suggests that the shorter peptides aurein 1.2 and citropin 1.1 act via a detergent-like mechanism because they can induce high local, but not long-range curvature, whereas the longer peptides maculatin 1.1 and caerin 1.1 require longer range curvature to fold and thus bind to and stabilize transmembrane pores

A Common Model for Cytokine Receptor Activation: Combined Scissor-Like Rotation and Self-Rotation of Receptor Dimer Induced by Class I Cytokine

The precise mechanism by which the binding of a class I cytokine to the extracellular domain of its corresponding receptor transmits a signal through the cell membrane remains unclear. Receptor activation involves a cytokine-receptor complex with a 1∶2 stoichiometry. Previously we used our transient-complex theory to calculate the rate constant of the initial cytokine-receptor binding to form a 1∶1 complex. Here we computed the binding pathway leading to the 1∶2 activation complex. Three cytokine systems (growth hormone, erythropoietin, and prolactin) were studied, and the focus was on the binding of the extracellular domain of the second receptor molecule after forming the 1∶1 complex. According to the transient-complex theory, translational and rotation diffusion of the binding entities bring them together to form a transient complex, which has near-native relative separation and orientation but not the short-range specific native interactions. Subsequently conformational rearrangement leads to the formation of the native complex. We found that the changes in relative orientations between the two receptor molecules from the transient complex to the 1∶2 native complex are similar for the three cytokine-receptor systems. We thus propose a common model for receptor activation by class I cytokines, involving combined scissor-like rotation and self-rotation of the two receptor molecules. Both types of rotations seem essential: the scissor-like rotation separates the intracellular domains of the two receptor molecules to make room for the associated Janus kinase molecules, while the self-rotation allows them to orient properly for transphosphorylation. This activation model explains a host of experimental observations. The transient-complex based approach presented here may provide a strategy for designing antagonists and prove useful for elucidating activation mechanisms of other receptors

The ELBA Force Field for Coarse-Grain Modeling of Lipid Membranes

A new coarse-grain model for molecular dynamics simulation of lipid membranes is presented. Following a simple and conventional approach, lipid molecules are modeled by spherical sites, each representing a group of several atoms. In contrast to common coarse-grain methods, two original (interdependent) features are here adopted. First, the main electrostatics are modeled explicitly by charges and dipoles, which interact realistically through a relative dielectric constant of unity (). Second, water molecules are represented individually through a new parametrization of the simple Stockmayer potential for polar fluids; each water molecule is therefore described by a single spherical site embedded with a point dipole. The force field is shown to accurately reproduce the main physical properties of single-species phospholipid bilayers comprising dioleoylphosphatidylcholine (DOPC) and dioleoylphosphatidylethanolamine (DOPE) in the liquid crystal phase, as well as distearoylphosphatidylcholine (DSPC) in the liquid crystal and gel phases. Insights are presented into fundamental properties and phenomena that can be difficult or impossible to study with alternative computational or experimental methods. For example, we investigate the internal pressure distribution, dipole potential, lipid diffusion, and spontaneous self-assembly. Simulations lasting up to 1.5 microseconds were conducted for systems of different sizes (128, 512 and 1058 lipids); this also allowed us to identify size-dependent artifacts that are expected to affect membrane simulations in general. Future extensions and applications are discussed, particularly in relation to the methodology's inherent multiscale capabilities

Effect of H3O+ on the Structure and Dynamics of Water at the Interface with Phospholipid Bilayers.

This study investigates the effect of hydronium ions (H3O+) on the structure and dynamics of water at the interface of a phospholipid bilayer using molecular dynamics simulations of a POPC bilayer in the presence and absence of H3O+ ions. From these simulations, the survival probability, hydrogen bond lifetimes, orientation relaxation, and angular distribution of interfacial water, at increasing distances from the membrane surface, were calculated. Simulations of POPC in the absence of H3O+ ions reproduce previously reported deviations of interfacial water from the properties of bulk water. Our results show that in the presence of H3O+, these deviations are even more pronounced with the strongest effects seen in the survival probability and orientation relaxation. To further investigate the effect of the H3O+-induced reduction of area per lipid on interfacial water, we carried out simulations where H3O+ ions were removed, but the area per lipid was fixed to the values seen in the presence of H3O+. The combined findings from our study suggest that the presence of H3O+ ions affects the properties of interfacial water, accentuates the deviation from bulk properties, and extends the long-range effect of these deviations further away from the membrane surface

The effect of H3O+ on the membrane morphology and hydrogen bonding of a phospholipid bilayer.

At the 2017 meeting of the Australian Society for Biophysics, we presented the combined results from two recent studies showing how hydronium ions (H3O+) modulate the structure and ion permeability of phospholipid bilayers. In the first study, the impact of H3O+ on lipid packing had been identified using tethered bilayer lipid membranes in conjunction with electrical impedance spectroscopy and neutron reflectometry. The increased presence of H3O+ (i.e. lower pH) led to a significant reduction in membrane conductivity and increased membrane thickness. A first-order explanation for the effect was assigned to alterations in the steric packing of the membrane lipids. Changes in packing were described by a critical packing parameter (CPP) related to the interfacial area and volume and shape of the membrane lipids. We proposed that increasing the concentraton of H3O+ resulted in stronger hydrogen bonding between the phosphate oxygens at the water-lipid interface leading to a reduced area per lipid and slightly increased membrane thickness. At the meeting, a molecular model for these pH effects based on the result of our second study was presented. Multiple μs-long, unrestrained molecular dynamic (MD) simulations of a phosphatidylcholine lipid bilayer were carried out and showed a concentration dependent reduction in the area per lipid and an increase in bilayer thickness, in agreement with experimental data. Further, H3O+ preferentially accumulated at the water-lipid interface, suggesting the localised pH at the membrane surface is much lower than the bulk bathing solution. Another significant finding was that the hydrogen bonds formed by H3O+ ions with lipid headgroup oxygens are, on average, shorter in length and longer-lived than the ones formed in bulk water. In addition, the H3O+ ions resided for longer periods in association with the carbonyl oxygens than with either phosphate oxygen in lipids. In summary, the MD simulations support a model where the hydrogen bonding capacity of H3O+ for carbonyl and phosphate oxygens is the origin of the pH-induced changes in lipid packing in phospholipid membranes. These molecular-level studies are an important step towards a better understanding of the effect of pH on biological membranes

Gli esami di avvocato tra garanzie procedimentali e tutela giurisdizionale

Published: August 5, 2014The peptides AM1 and Lac21E self-organize into switchable films at an air-water interface. In an earlier study, it was proposed that both AM1 and Lac21E formed monolayers of α-helical peptides based on consistency with neutron reflectivity data. In this article, molecular dynamics simulations of assemblies of helical and nonhelical AM1 and Lac21E at an air-water interface suggest some tendency for the peptides to spontaneously adopt an α-helical conformation. However, irrespective of the structure of the peptides, the simulations reproduced not only the structural properties of the films (thickness and distribution of the hydrophobic and hydrophilic amino acids) but also the experimental neutron reflectivity measurements at different contrast variations. This suggests that neutron reflectometry alone cannot be used to determine the structure of the peptides in this case. However, together with molecular dynamics simulations, it is possible to obtain a detailed understanding of peptide films at an atomic level.Ying Xue, Lizhong He, Anton P. J. Middelberg, Alan E. Mark, and David Poge

Activating the prolactin receptor: Effect of the ligand on the conformation of the extracellular domain

The prolactin receptor resides on the surface of the cell as a preformed dimer. This suggests that cell signaling is triggered by conformational changes within the extracellular domain of the receptors. Here, by using atomistic molecular dynamics simulations, we show that the removal of the ligand placental lactogen from the dimeric form of the prolactin receptor results in a relative reorientation of the two extracellular domains by 20−30°, which corresponds to a clockwise rotation of the domains with respect to each other. Such a mechanism of activation for the prolactin receptor is similar to that proposed previously in the case of the growth hormone receptor. In addition to the effect of the removal of the ligand, the mechanical coupling between the extracellular and transmembrane domains within a model membrane was also examined. Copyright © 2010 American Chemical Societ

The effect of H<inf>3</inf>O⁺ on the membrane morphology and hydrogen bonding of a phospholipid bilayer

© 2018, International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature. At the 2017 meeting of the Australian Society for Biophysics, we presented the combined results from two recent studies showing how hydronium ions (H3O+) modulate the structure and ion permeability of phospholipid bilayers. In the first study, the impact of H3O+ on lipid packing had been identified using tethered bilayer lipid membranes in conjunction with electrical impedance spectroscopy and neutron reflectometry. The increased presence of H3O+ (i.e. lower pH) led to a significant reduction in membrane conductivity and increased membrane thickness. A first-order explanation for the effect was assigned to alterations in the steric packing of the membrane lipids. Changes in packing were described by a critical packing parameter (CPP) related to the interfacial area and volume and shape of the membrane lipids. We proposed that increasing the concentraton of H3O+ resulted in stronger hydrogen bonding between the phosphate oxygens at the water–lipid interface leading to a reduced area per lipid and slightly increased membrane thickness. At the meeting, a molecular model for these pH effects based on the result of our second study was presented. Multiple µs-long, unrestrained molecular dynamic (MD) simulations of a phosphatidylcholine lipid bilayer were carried out and showed a concentration dependent reduction in the area per lipid and an increase in bilayer thickness, in agreement with experimental data. Further, H3O+ preferentially accumulated at the water–lipid interface, suggesting the localised pH at the membrane surface is much lower than the bulk bathing solution. Another significant finding was that the hydrogen bonds formed by H3O+ ions with lipid headgroup oxygens are, on average, shorter in length and longer-lived than the ones formed in bulk water. In addition, the H3O+ ions resided for longer periods in association with the carbonyl oxygens than with either phosphate oxygen in lipids. In summary, the MD simulations support a model where the hydrogen bonding capacity of H3O+ for carbonyl and phosphate oxygens is the origin of the pH-induced changes in lipid packing in phospholipid membranes. These molecular-level studies are an important step towards a better understanding of the effect of pH on biological membranes