Influence Of Electrostatics Research Articles

Electrostatics Choreographs the Aggregation Dynamics of Full-Length TDP-43 via a Monomeric Amyloid Precursor.

TDP-43 is a ubiquitously expressed, multidomain functional protein that is distinctively known to form aggregates in many fatal neurodegenerative disorders. However, the information for arresting TDP-43 aggregation is missing due to a lack of understanding of the molecular mechanism of the aggregation and structural properties of TDP-43. TDP-43 is inherently prone to aggregation and has minimal protein solubility. Multiple studies have been performed on the smaller parts of TDP-43 or the full-length protein attached to a large solubilization tag. However, the presence of co-solutes or solubilization tags is observed to interfere with the molecular properties and aggregation mechanism of full-length TDP-43. Notably, this study populated and characterized the native, dimeric state of TDP-43 without the interference of co-solutes or protein modifications. We observed that the electrostatics of the local environment is capable of the partial unfolding and monomerization of the native dimeric state of TDP-43 into an amyloidogenic molten globule. By employing the tools of thermodynamics and kinetics, we reveal the structural characteristics and temporal order of the early intermediates and transition states during the transition of the molten globule to β-rich, amyloid-like aggregates of TDP-43, which is governed by the electrostatics of the environment. The current advanced understanding of the nature of native and early aggregation-prone intermediates, early steps, and the influence of electrostatics in TDP-43 aggregation is essential for drug design.

Bounce and contact mode regimes for drop impact on smooth surfaces: The influence of gas kinetics and electrostatics

When liquid drops impact on solid surfaces, an air layer forms in between the drop and the surface, acting as a cushion to mitigate the impact. In this work, we focus on delineating the bounce and contact mode regimes of impacting drops on smooth surfaces, specifically discerning whether drops rebound from the air layer or make contact with the solid surfaces, and pinpointing the precise contact modes between the drop and solid surfaces by resolving the gas film evolution and rupture. Our simulation model incorporates gas kinetics and electrostatics effects, both of which have been validated by experiments documented in the literature or theoretical models regarding thin film instabilities. We undertake a comprehensive review and categorization of the contact modes and elucidate how they change under different conditions of impact velocities, ambient pressures, and electric field intensities. We also provide some perspectives on the regime map for the lubricated surfaces, which contains an unresolved issue that the critical Weber number for bouncing-wetting transition is significantly reduced compared to the solid smooth surfaces like mica. These insights have noteworthy practical implications offering guidance for a wide range of scenarios, from normal-pressure environments to low-pressure conditions at high altitudes, encompassing high electric field conditions such as nanogenerators as well as low electric field conditions resembling glass surfaces with static electricity.

Dilute polyelectrolyte solutions: recent progress and open questions.

Polyelectrolytes are a class of polymers possessing ionic groups on their repeating units. Since counterions can dissociate from the polymer backbone, polyelectrolyte chains are strongly influenced by electrostatic interactions. As a result, the physical properties of polyelectrolyte solutions are significantly different from those of electrically neutral polymers. The aim of this article is to highlight key results and some outstanding questions in the polyelectrolyte research from recent literature. We focus on the influence of electrostatics on conformational and hydrodynamic properties of polyelectrolyte chains. A compilation of experimental results from the literature reveals significant disparities with theoretical predictions. We also discuss a new class of polyelectrolytes called poly(ionic liquid)s that exhibit unique physical properties in comparison to ordinary polyelectrolytes. We conclude this review by listing some key research challenges in order to fully understand the conformation and dynamics of polyelectrolytes in solutions.

Computational Characterization of the Reactivity of Compound I in Unspecific Peroxygenases.

Unspecific peroxygenases (UPOs) are emerging as promising biocatalysts for selective oxyfunctionalization of unactivated C-H bonds. However, their potential in large-scale synthesis is currently constrained by suboptimal chemical selectivity. Improving the selectivity of UPOs requires a deep understanding of the molecular basis of their catalysis. Recent molecular simulations have sought to unravel UPO's selectivity and inform their design principles. However, most of these studies focused on substrate-binding poses. Few researchers have investigated how the reactivity of CpdI, the principal oxidizing intermediate in the catalytic cycle, influences selectivity in a realistic protein environment. Moreover, the influence of protein electrostatics on the reaction kinetics of CpdI has also been largely overlooked. To bridge this gap, we used multiscale simulations to interpret the regio- and enantioselective hydroxylation of the n-heptane substrate catalyzed by Agrocybe aegerita UPO (AaeUPO). We comprehensively characterized the energetics and kinetics of the hydrogen atom-transfer (HAT) step, initiated by CpdI, and the subsequent oxygen rebound step forming the product. Notably, our approach involved both free energy and potential energy evaluations in a quantum mechanics/molecular mechanics (QM/MM) setting, mitigating the dependence of results on the choice of initial conditions. These calculations illuminate the thermodynamics and kinetics of the HAT and oxygen rebound steps. Our findings highlight that both the conformational selection and the distinct chemical reactivity of different substrate hydrogen atoms together dictate the regio- and enantio-selectivity. Building on our previous study of CpdI's formation in AaeUPO, our results indicate that the HAT step is the rate-limiting step in the overall catalytic cycle. The subsequent oxygen rebound step is swift and retains the selectivity determined by the HAT step. We also pinpointed several polar and charged amino acid residues whose electrostatic potentials considerably influence the reaction barrier of the HAT step. Notably, the Glu196 residue is pivotal for both the CpdI's formation and participation in the HAT step. Our research offers in-depth insights into the catalytic cycle of AaeUPO, which will be instrumental in the rational design of UPOs with enhanced properties.

Forward coupling approach to model time periodic piezoelectric problems

AbstractMicro electro‐mechanical systems (MEMS), such as piezoelectric loudspeakers are widely used for ultrasound applications. Designing advanced MEMS can be challenging, since nonlinear physical effects may have a significant impact. Piezoelectricity couples the mechanical and electrostatic field directly via the material law, which is often nonlinear and hysteretic. In many applications, only the steady‐state solution is of interest. The nonlinear electrostatic response to periodic forcing can be found directly in the frequency domain with the help of harmonic balancing and an alternating time frequency scheme. For certain problems and boundary conditions it might be sufficient to only assume forward coupling, i.e. one first computes the nonlinear hysteretic electrostatic field and then, use the resulting electric field and polarization to define piezoelectrically induced strains that excite the mechanical system. There are several ways to incorporate the piezoelectrically induced strains into the mechanical system. One way is to use a constant piezoelectric coupling tensor, which is used in Voigt's linear piezoelectric model. We use a phenomenological model for the piezoelectric coupling tensor, linearly scaling the coupling tensor based on the magnitude of the polarization. In this model, we neglect mechanical depolarization under the assumption that the prevailing mechanical stresses are small and a strong applied electric field enforces a certain polarization. The errors made by the forward coupling are estimated and compared with Voigt's linear piezoelectric model, for which direct coupling is used. The result of the forward coupling approach agrees well with the directly coupled results, and it needs less computational effort. Due to the phenomenological model for the piezoelectric coupling tensor, the response of the mechanical system changes and reflects the influence of nonlinear electrostatics.

Brunner syndrome caused by point mutation explained by multiscale simulation of enzyme reaction

Brunner syndrome is a disorder characterized by intellectual disability and impulsive, aggressive behavior associated with deficient function of the monoamine oxidase A (MAO-A) enzyme. These symptoms (along with particularly high serotonin levels) have been reported in patients with two missense variants in MAO-A (p.R45W and p.E446K). Herein, we report molecular simulations of the rate-limiting step of MAO-A-catalyzed serotonin degradation for these variants. We found that the R45W mutation causes a 6000-fold slowdown of enzymatic function, whereas the E446K mutation causes a 450-fold reduction of serotonin degradation rate, both of which are practically equivalent to a gene knockout. In addition, we thoroughly compared the influence of enzyme electrostatics on the catalytic function of both the wild type MAO-A and the p.R45W variant relative to the wild type enzyme, revealing that the mutation represents a significant electrostatic perturbation that contributes to the barrier increase. Understanding genetic disorders is closely linked to understanding the associated chemical mechanisms, and our research represents a novel attempt to bridge the gap between clinical genetics and the underlying chemical physics.

The competing influence of surface roughness, hydrophobicity, and electrostatics on protein dynamics on a self-assembled monolayer.

Surface morphology, in addition to hydrophobic and electrostatic effects, can alter how proteins interact with solid surfaces. Understanding the heterogeneous dynamics of protein adsorption on surfaces with varying roughness is experimentally challenging. In this work, we use single-molecule fluorescence microscopy to study the adsorption of α-lactalbumin protein on the glass substrate covered with a self-assembled monolayer (SAM) with varying surface concentrations. Two distinct interaction mechanisms are observed: localized adsorption/desorption and continuous-time random walk (CTRW). We investigate the origin of these two populations by simultaneous single-molecule imaging of substrates with both bare glass and SAM-covered regions. SAM-covered areas of substrates are found to promote CTRW, whereas glass surfaces promote localized motion. Contact angle measurements and atomic force microscopy imaging show that increasing SAM concentration results in both increasing hydrophobicity and surface roughness. These properties lead to two opposing effects: increasing hydrophobicity promotes longer protein flights, but increasing surface roughness suppresses protein dynamics resulting in shorter residence times. Our studies suggest that controlling hydrophobicity and roughness, in addition to electrostatics, as independent parameters could provide a means to tune desirable or undesirable protein interactions with surfaces.

Energetic Basis and Design of Enzyme Function Demonstrated Using GFP, an Excited-State Enzyme.

The past decades have witnessed an explosion of de novo protein designs with a remarkable range of scaffolds. It remains challenging, however, to design catalytic functions that are competitive with naturally occurring counterparts as well as biomimetic or nonbiological catalysts. Although directed evolution often offers efficient solutions, the fitness landscape remains opaque. Green fluorescent protein (GFP), which has revolutionized biological imaging and assays, is one of the most redesigned proteins. While not an enzyme in the conventional sense, GFPs feature competing excited-state decay pathways with the same steric and electrostatic origins as conventional ground-state catalysts, and they exert exquisite control over multiple reaction outcomes through the same principles. Thus, GFP is an "excited-state enzyme". Herein we show that rationally designed mutants and hybrids that contain environmental mutations and substituted chromophores provide the basis for a quantitative model and prediction that describes the influence of sterics and electrostatics on excited-state catalysis of GFPs. As both perturbations can selectively bias photoisomerization pathways, GFPs with fluorescence quantum yields (FQYs) and photoswitching characteristics tailored for specific applications could be predicted and then demonstrated. The underlying energetic landscape, readily accessible via spectroscopy for GFPs, offers an important missing link in the design of protein function that is generalizable to catalyst design.

Voltage-Dependent Transport of Neutral Solutes through Nanopores: A Molecular View.

The permeation of (neutral) molecules through nanopores in the presence of external voltages depends on several factors including pore electrostatics, electrophoretic force, and electro-osmotic drag. In earlier single-channel electrophysiology experiments, voltage-dependent asymmetric transport of neutral α-cyclodextrin (α-CD) molecules through the biological nanopore ΔCymA was observed. The voltage-dependent ion-associated flow of water, the so-called electro-osmotic flow, has been suggested to be the key factor behind the observed asymmetric behavior. The influence of pore electrostatics and electrophoretic force and their interplay with the electro-osmotic drag with varying buffers and voltages has not yet been analyzed at the molecular level. Hence, the detailed physical mechanism behind this intriguing permeation process is in part still unclear. In the present study, we have performed 36 μs all-atom free energy calculations by combining applied-field molecular dynamics simulations with metadynamics techniques. The influence of several ionic conditions as well as external voltages on the permeation of α-CD molecules across the ΔCymA pore has been investigated. To decipher the thermodynamic and kinetic details, the lowest energy paths and the permeation times for α-CD translocation have been estimated. In the presence of KCl or MgCl2 salts, the charge of the cations is found to control the direction and magnitude of the electro-osmotic flow, which in turn strongly affects α-CD permeation. Overall, the present findings significantly improve the fundamental understanding of the voltage-dependent transport of neutral solutes across nanopores.

Methyltransferase CheR binds to its chemoreceptor substrates independent of their signaling conformation yet modifies them differentially.

Methylation of specific chemoreceptor glutamyl residues by methyltransferase CheR mediates sensory adaptation and gradient sensing in bacterial chemotaxis. Enzyme action is a function of chemoreceptor signaling conformation: kinase-off receptors are more readily methylated than kinase-on, a feature central to adaptational and gradient-sensing mechanisms. Differential enzyme action could reflect differential binding, catalysis or both. We investigated by measuring CheR binding to kinase-off and kinase-on forms of Escherichia coli aspartate receptor Tar deleted of its CheR-tethering, carboxyl terminus pentapeptide. This allowed characterization of the low-affinity binding of enzyme to the substrate receptor body, otherwise masked by high-affinity interaction with pentapeptide. We quantified the low-affinity protein-protein interactions by determining kinetic rate constants of association and dissociation using bio-layer interferometry and from those values calculating equilibrium constants. Whether Tar signaling conformations were shifted by ligand occupancy or adaptational modification, there was little or no difference between the two signaling conformations in kinetic or equilibrium parameters of enzyme-receptor binding. Thus, differential methyltransferase action does not reflect differential binding. Instead, the predominant determinants of binding must be common to different signaling conformations. Characterization of the dependence of association rate constants on Deybe length, a measure of the influence of electrostatics, implicated electrostatic interactions as a common binding determinant. Taken together, our observations indicate that differential action of methyltransferase on kinase-off and kinase-on chemoreceptors is not the result of differential binding and suggest it reflects differential catalytic propensity. Differential catalysis rather than binding could well be central to other enzymes distinguishing alternative conformations of protein substrates.

Visible and infrared photocurrent enhancement in a graphene-silicon Schottky photodetector through surface-states and electric field engineering

The design of efficient graphene-silicon (GSi) Schottky junction photodetectors requires detailed understanding of the spatial origin of the photoresponse. Scanning-photocurrent-microscopy (SPM) studies have been carried out in the visible wavelengths regions only, in which the response due to silicon is dominant. Here we present comparative SPM studies in the visible ( nm) and infrared ( nm) wavelength regions for a number of GSi Schottky junction photodetector architectures, revealing the photoresponse mechanisms for silicon and graphene dominated responses, respectively, and demonstrating the influence of electrostatics on the device performance. Local electric field enhancement at the graphene edges leads to a more than ten-fold increased photoresponse compared to the bulk of the graphene-silicon junction. Intentional design and patterning of such graphene edges is demonstrated as an efficient strategy to increase the overall photoresponse of the devices, leading to a more than two-fold responsivity enhancement under global illumination to 5 10−6 A W−1 at a wavelength of 1650 nm for the patterned device compared to the unpatterned device. Complementary simulations and modeling illuminate observed effects and highlight the importance of considering graphene’s shape and pattern and device geometry in the device design.

Electrostatic Influence on Photoisomerization in Bacteriorhodopsin and Halorhodopsin.

Bacteriorhodopsin (bR) and halorhodopsin (hR) are both membrane proteins that transport ions across the cell membrane in halobacteria. Their ion transport function is triggered by photoactivated isomerization of the retinal protonated Schiff base (RPSB) chromophore. In spite of their similar structures, bR and hR exhibit widely differing RPSB isomerization rates and quantum yields (with bR being both faster and more efficient than hR). Previous simulations of photoisomerization in bR and hR using ab initio multiple spawning (AIMS) with QM/MM have successfully reproduced the experimentally observed ordering of quantum yields and isomerization rates, but the origin of these differences remains elusive. Here we investigate the role of electrostatic interactions in the protein pocket surrounding RPSB. We probe the influence of protein electrostatics by modifying the charge of the complex counterion in bR/hR to be more/less negative than the native state. We find that such modifications lead to bR-like behavior in hR and vice versa. This demonstrates the crucial role of electrostatic interactions in controlling the outcome of RPSB photoisomerization.

Specific co-ion sorption and diffusion properties influence membrane permselectivity

The apparent permselectivity of three cation exchange membranes (CEMs) was measured using four monovalent strong electrolytes (sodium chloride, sodium bromide, sodium nitrate and sodium perchlorate). The salt (co-ion) sorption and diffusion coefficients of a crosslinked sulfonated polymer, based on the sodium salt form of 2-acrylamido-2-methylpropane sulfonic acid (AMPS), were measured to describe the influence of sorption and diffusion properties on apparent permselectivity. Three models were used (in conjunction with electroneutrality and thermodynamic equilibrium conditions) to probe the influence of electrostatic and dispersion energy forces on specific co-ion sorption. Dispersion forces appear to be important for capturing specific co-ion sorption properties. A model combining the Mackie and Meares hindered diffusion theory and Manning's counter-ion condensation theory was used to explore the influence of electrostatics and polymer tortuosity on co-ion diffusion. Ion-polymer complexation interactions between sodium perchlorate and the poly(ethylene oxide)-based crosslinker used in the sulfonated polymer significantly influenced sorption and diffusion properties. The occurrence of these ion-polymer complexes was supported by salt sorption measurements made on three uncharged, crosslinked poly(ethylene oxide)-containing polymers with 3, 10, or 13 ethylene oxide repeat units between crosslinks. Ion specific sorption, diffusion, and ion-polymer complexation phenomena influence apparent permselectivity properties of charged polymers, and the sorption and complexation phenomena appear to affect apparent permselectivity properties to a greater extent compared to ion specific diffusion effects other than size-based differences.

Binding, folding and insertion of a β-hairpin peptide at a lipid bilayer surface: Influence of electrostatics and lipid tail packing

Antimicrobial peptides (AMPs) act as host defenses against microbial pathogens. Here we investigate the interactions of SVS-1 (KVKVKVKVdPlPTKVKVKVK), an engineered AMP and anti-cancer β-hairpin peptide, with lipid bilayers using spectroscopic studies and atomistic molecular dynamics simulations. In agreement with literature reports, simulation and experiment show preferential binding of SVS-1 peptides to anionic over neutral bilayers. Fluorescence and circular dichroism studies of a Trp-substituted SVS-1 analogue indicate, however, that it will bind to a zwitterionic DPPC bilayer under high-curvature conditions and folds into a hairpin. In bilayers formed from a 1:1 mixture of DPPC and anionic DPPG lipids, curvature and lipid fluidity are also observed to promote deeper insertion of the fluorescent peptide. Simulations using the CHARMM C36m force field offer complementary insight into timescales and mechanisms of folding and insertion. SVS-1 simulated at an anionic mixed POPC/POPG bilayer folded into a hairpin over a microsecond, the final stage in folding coinciding with the establishment of contact between the peptide's valine sidechains and the lipid tails through a “flip and dip” mechanism. Partial, transient folding and superficial bilayer contact are seen in simulation of the peptide at a zwitterionic POPC bilayer. Only when external surface tension is applied does the peptide establish lasting contact with the POPC bilayer. Our findings reveal the influence of disruption to lipid headgroup packing (via curvature or surface tension) on the pathway of binding and insertion, highlighting the collaborative effort of electrostatic and hydrophobic interactions on interaction of SVS-1 with lipid bilayers.

Interaction of dextran derivatives with lipid monolayers and the consequential modulation of the film properties

Polysaccharides have been associated with various biological functions through their binding to membranes, but their specific role is still under debate. The aim of this work was to study the interaction of cationic and anionic polysaccharides with anionic and zwitterionic monolayers, at different subphase compositions, thus analyzing the influence of electrostatics on the interaction. The consequent effect of the polymer-lipid binding on the film properties was studied, with special interest in monolayer dynamics. The results indicate that electrostatic interactions play an important role in polymer-membrane affinity, and that the polymers formed a sub-layer, which increased the shear viscosity of the interface. The interacting polymer, even when it did not penetrate the lipid film, induced a polymer-like behavior of the monolayer regarding its dynamics: the whole film (polymer+lipid) became very viscous. As a consequence, the dynamic of the membrane was affected, thus inducing changes in the film topography, although the energetics for phase transition and the stability of each phase were modified slightly or not at all.

Dynamic self-assembly of charged colloidal strings and walls in simple fluid flows.

Colloidal particles can self-assemble into various ordered structures in fluid flows that have potential applications in biomedicine, materials synthesis and encryption. These dynamic processes are also of fundamental interest for probing the general principles of self-assembly under non-equilibrium conditions. Here, we report a simple microfluidic experiment, where charged colloidal particles self-assemble into flow-aligned 1D strings with regular particle spacing near a solid boundary. Using high-speed confocal microscopy, we systematically investigate the influence of flow rates, electrostatics and particle polydispersity on the observed string structures. By studying the detailed dynamics of stable flow-driven particle pairs, we quantitatively characterize interparticle interactions. Based on the results, we construct a simple model that explains the intriguing non-equilibrium self-assembly process. Our study shows that the colloidal strings arise from a delicate balance between attractive hydrodynamic coupling and repulsive electrostatic interaction between particles. Finally, we demonstrate that, with the assistance of transverse electric fields, a similar mechanism also leads to the formation of 2D colloidal walls.

Theoretical investigation of the interactions between the π‐systems of molecular organic semiconductors and an analysis of the contributions of repulsion and electrostatics

A concept for the interactions between π‐systems is necessary to understand a number of phenomena in modern material sciences such as supramolecular properties and self‐assembly. In the present article, we investigate the intermolecular interaction energies between organic semiconductors with extended π‐systems using SAPT (symmetry‐adapted perturbation theory), LMO‐EDA (localized molecular orbital energy decomposition analysis), DFT‐D (density functional theory including dispersion corrections), and force‐field approaches. Both apolar organic molecules such as acenes and highly polarized π‐systems of merocyanines and squaraines were used to probe the influence of electrostatics on the shape of the potential energy surfaces (PES) governing the geometric structures of aggregates. Our results reveal that the shapes of the PESs result from variations in the short‐range, highly specific repulsion forces even for highly polar molecules. Using distributed quadrupoles, we show that it is nevertheless possible to mimic the intermolecular potentials with electrostatics. This is also possible with van‐der‐Waals potentials and a simple overlap‐based force‐field ansatz based on the overlap between p‐orbitals. © 2016 Wiley Periodicals, Inc.

Influence of Electrostatics on Small Molecule Flux through a Protein Nanoreactor.

Nature uses protein compartmentalization to great effect for control over enzymatic pathways, and the strategy has great promise for synthetic biology. In particular, encapsulation in nanometer-sized containers to create nanoreactors has the potential to elicit interesting, unexplored effects resulting from deviations from well-understood bulk processes. Self-assembled protein shells for encapsulation are especially desirable for their uniform structures and ease of perturbation through genetic mutation. Here, we use the MS2 capsid, a well-defined porous 27 nm protein shell, as an enzymatic nanoreactor to explore pore-structure effects on substrate and product flux during the catalyzed reaction. Our results suggest that the shell can influence the enzymatic reaction based on charge repulsion between small molecules and point mutations around the pore structure. These findings also lend support to the hypothesis that protein compartments modulate the transport of small molecules and thus influence metabolic reactions and catalysis in vitro.

Topological states inα−Snand HgTe quantum wells: A comparison ofab initioresults

Both $\ensuremath{\alpha}\text{-Sn}$ and HgTe are expected to have similar topological properties because of their inverted band structure and zero-gap character. We investigate how the different crystal symmetries and the bonding to barrier materials act to the quantum phase transition versus the thickness of the corresponding quantum well (QW) structures. They are simulated by ${(\text{SnSn})}_{N}{(\text{CdTe})}_{M}$ and ${(\text{HgTe})}_{N}{(\text{CdTe})}_{M}(110)$ superlattices. Their electronic structures and eigenstates are studied by means of first-principles calculations using the modified Becke-Johnson exchange-correlation functional and spin-orbit interaction. Significant differences are observed for the two QW materials. A topological transition between trivial insulator and quantum spin Hall phase together with the formation of topologically protected edge states are observed in the case of HgTe QWs, while these features are considerably modified for $\ensuremath{\alpha}\text{-Sn}$. The different behaviors are discussed in the light of the different symmetry, spin-orbit interaction, and interface bonding. For a better understanding of the influence of the interface electrostatics also results for ${(\text{HgTe})}_{N}{(\text{InSb})}_{M}(110)$ systems are discussed.

Membrane Structure Correlates to Function of LLP2 on the Cytoplasmic Tail of HIV-1 gp41 Protein

Mutation studies previously showed that the lentivirus lytic peptide (LLP2) sequence of the cytoplasmic C-terminal tail of the HIV-1 gp41 envelope protein inhibited viral-initiated T-cell death and T-cell syncytium formation, at which time in the HIV life cycle the gp41 protein is embedded in the T-cell membrane. In striking contrast, the mutants did not affect virion infectivity, during which time the gp41 protein is embedded in the HIV envelope membrane. To examine the role of LLP2/membrane interactions, we applied synchrotron x-radiation to determine structure of hydrated membranes. We focused on WT LLP2 peptide (+3 charge) and MX2 mutant (−1 charge) with membrane mimics for the T-cell and the HIV-1 membranes. To investigate the influence of electrostatics, cholesterol content, and peptide palmitoylation, we also studied three other LLP2 variants and HIV-1 mimics without negatively charged lipids or cholesterol as well as extracted HIV-1 lipids. All LLP2 peptides bound strongly to T-cell membrane mimics, as indicated by changes in membrane structure and bending. In contrast, none of the weakly bound LLP2 variants changed the HIV-1 membrane mimic structure or properties. This correlates well with, and provides a biophysical basis for, previously published results that reported lack of a mutant effect in HIV virion infectivity in contrast to an inhibitory effect in T-cell syncytium formation. It shows that interaction of LLP2 with the T-cell membrane modulates biological function.