Search

Human voltage-gated proton (hHv1) channels are crucial for regulating essential biological processes such as immune cell respiratory burst, sperm capacitation, and cancer cell migration. Despite the significant concentration difference between protons and other ions in physiological conditions, hHv1 demonstrates remarkable proton selectivity. Our calculations of single-proton, cation, and anion permeation free energy profiles quantitatively demonstrate that the proton selectivity of the wild-type channel originates from its strong proton affinity via the titration of the key residues D112 and D174, although the channel imposes similar kinetic blocking effects for protons compared to other ions. A two-proton knock-on model is proposed to mathematically explain the electrophysiological measurements of the pH-dependent proton conductance in the conductive state. Moreover, it is shown that the anion selectivity of the D112N mutant channel is tied to impaired proton transport and substantial anion leakage. [ABSTRACT FROM AUTHOR]

We present a study of four monoterpene isomers (limonene, γ-terpinene, terpinolene, and α-pinene) that are prevalent in indoor environments and their interaction with the hydroxylated SiO2 surface, a model for the glass surface, by combining infrared spectroscopy and computational simulations. These isomers are molecularly adsorbed onto SiO2 through π-hydrogen bonds with surface hydroxyl groups. However, experimental results suggest that the strength of interaction of these compounds with the SiO2 surface varies for each isomer, with α-pinene showing the weakest interaction. This observation is supported by molecular dynamics simulations that α-pinene adsorbed on the SiO2 surface has lower free energy of desorption and a lower mass accommodation coefficient compared to other isomers. Additionally, our ab initio molecular dynamics simulations show lower π-hydrogen bonding probabilities for α-pinene compared to the other three constitutional isomers. Importantly, these interactions are most likely present for a range of other systems involving organic compounds and solid surfaces and, thus, provide a thorough framework for comparing the interactions of organic molecules on indoor relevant surfaces. [ABSTRACT FROM AUTHOR]

The molecular basis underlying the rich phase behavior of globular proteins remains poorly understood. We use atomistic multiscale molecular simulations to model the solution‐state conformational dynamics and interprotein interactions of γD‐crystallin and its P23T‐R36S mutant, which drastically limits the protein solubility, at both infinite dilution and at a concentration where the mutant fluid phase and crystalline phase coexist. We find that while the mutant conserves the protein fold, changes to the surface exposure of residues in the neighborhood of residue‐36 enhance protein–protein interactions and develop specific protein–protein contacts found in the protein crystal lattice. [ABSTRACT FROM AUTHOR]

There are currently no drugs known to rescue the function of Kv1.1 voltage-gated potassium channels carrying loss-of-function sequence variants underlying the inherited movement disorder, Episodic Ataxia 1 (EA1). The Kwakwaka'wakw First Nations of the Pacific Northwest Coast used Fucus gardneri (bladderwrack kelp), Physocarpus capitatus (Pacific ninebark) and Urtica dioica (common nettle) to treat locomotor ataxia. Here, we show that extracts of these plants enhance wild-type Kv1.1 current, especially at subthreshold potentials. Screening of their constituents revealed that gallic acid and tannic acid similarly augment wild-type Kv1.1 current, with submicromolar potency. Crucially, the extracts and their constituents also enhance activity of Kv1.1 channels containing EA1-linked sequence variants. Molecular dynamics simulations reveal that gallic acid augments Kv1.1 activity via a small-molecule binding site in the extracellular S1-S2 linker. Thus, traditional Native American ataxia treatments utilize a molecular mechanistic foundation that can inform small-molecule approaches to therapeutically correcting EA1 and potentially other Kv1.1-linked channelopathies. Drugs that rescue function of episodic ataxia 1 (EA1) mutant potassium channels are lacking. Here, Manville et al identify and describe the molecular basis for Native American botanical ataxia remedies that directly rescue EA1 mutant channels. [ABSTRACT FROM AUTHOR]

The compound 6-methyl-5-hepten-2-one (6-MHO) is a product of skin oil ozonolysis and is of significance in understanding the role of human occupants in the indoor environment. We present a joint computational and experimental study investigating the adsorption of 6-MHO on two model indoor relevant surfaces, SiO2, a model for a glass window, and TiO2, a component of paint and self-cleaning surfaces. Our classical force field-based molecular dynamics, ab initio molecular dynamics simulations, and FTIR absorption spectra indicate 6-MHO can adsorb on to both of these surfaces via hydrogen and π-hydrogen bonds and is quite stable due to the linear geometry of 6-MHO. Detailed analysis of 6-MHO on the SiO2 surface shows that relative humidity does not impact surface adsorption and adsorbed water does not displace 6-MHO from the hydroxylated SiO2 surface. Additionally, the desorption kinetics of 6-MHO from the hydroxylated SiO2 surface is compared to other compounds found in indoor environments and 6-MHO is shown to desorb with a first order rate constant that is approximately four times slower than that of limonene, but six times faster than that of carvone. In addition, our joint results indicate 6-MHO forms a stronger interaction with the TiO2 surface compared to the SiO2 surface. This study suggests that skin oil ozonolysis products can partition to indoor surfaces leading to the formation of organic films. [ABSTRACT FROM AUTHOR]

Limonene, a monoterpene, found in cleaning products and air fresheners can interact with a variety of surfaces in indoor environments. An oxidation product of limonene, carvone, has been reported to cause contact allergens. In this study, we have investigated the interactions of limonene and carvone with TiO2, a component of paint and self-cleaning surfaces, at 297 ± 1 K with FTIR spectroscopy and force field-based molecular dynamics and ab initio simulations. The IR absorption spectra and computational methods show that limonene forms π-hydrogen bonds with the surface O–H groups on the TiO2 surface and that carvone adsorbs on the TiO2 surface through a variety of molecular interactions including through carbonyl oxygen atoms with Ti4+ surface atoms, O–H hydrogen bonding (carbonyl O⋯HO) and π-hydrogen bonds with surface O–H groups. Furthermore, we investigated the effects of relative humidity (RH) on the adsorption of limonene and carvone on the TiO2 surface. The spectroscopic results show that the adsorbed limonene can be completely displaced by water at a relative humidity of ca. 50% RH (∼2 MLs of water) and that 25% of carvone is displaced at ca. 67% RH, which agrees with the calculated free energies of adsorption which show carvone more strongly adsorbs on the surface relative to limonene and thus would be harder to displace from the surface. Overall, this study shows how a monoterpene and its oxidation product interact with TiO2 and the impact of relative humidity on these interactions. [ABSTRACT FROM AUTHOR]

Cancerous tissues undergo extensive changes to their cellular environments that differentiate them from healthy tissues. These changes include changes in extracellular pH and Ca2+ concentrations, and the exposure of phosphatidylserine (PS) to the extracellular environment, which can modulate the interaction of peptides and proteins with the plasma membrane. Deciphering the molecular mechanisms of such interactions is critical for advancing the knowledge‐based design of cancer‐targeting molecular tools, such as pH‐low insertion peptide (pHLIP). Here, we explore the effects of PS, Ca2+, and peptide protonation state on the interactions of pHLIP with lipid membranes. Cellular studies demonstrate that exposed PS on the plasma membrane promotes pHLIP targeting. The magnitude of this effect is dependent on extracellular Ca2+ concentration, indicating that divalent cations play an important role in pHLIP targeting in vivo. The targeting mechanism is further explored with a combination of fluorescence and circular dichroism experiments in model membranes and microsecond‐timescale all‐atom molecular dynamics simulations. Our results demonstrate that Ca2+ is engaged in coupling peptide‐lipid interactions in the unprotonated transmembrane conformation of pHLIP. The simulations reveal that while the pH‐induced insertion leads to a strong depletion of PS around pHLIP, the Ca2+‐induced insertion has the opposite effect. Thus, extracellular levels of Ca2+ are crucial to linking cellular changes in membrane lipid composition with the selective targeting and insertion of pHLIP. The characterized Ca2+‐dependent coupling between pHLIP sidechains and PS provides atomistic insights into the general mechanism for lipid‐coupled regulation of protein‐membrane insertion by divalent cations. [ABSTRACT FROM AUTHOR]

Over the past decade, energy-dependent ambient pressure X-ray photoelectron spectroscopy (XPS) has emerged as a powerful analytical probe of the ion spatial distributions at the vapor (vacuum)- aqueous electrolyte interface. These experiments are often paired with complementary molecular dynamics (MD) simulations in an attempt to provide a complete description of the liquid interface. There is, however, no systematic protocol that permits a straightforward comparison of the two sets of results. XPS is an integrated technique that averages signals from multiple layers in a solution even at the lowest photoelectron kinetic energies routinely employed, whereas MD simulations provide a microscopic layer-by-layer description of the solution composition near the interface. Here, we use the National Institute of Standards and Technology database for the Simulation of Electron Spectra for Surface Analysis (SESSA) to quantitatively interpret atom-density profiles from MD simulations for XPS signal intensities using sodium and potassium iodide solutions as examples. We show that electron inelastic mean free paths calculated from a semi-empirical formula depend strongly on solution composition, varying by up to 30% between pure water and concentrated NaI. The XPS signal thus arises from different information depths in different solutions for a fixed photoelectron kinetic energy. XPS signal intensities are calculated using SESSA as a function of photoelectron kinetic energy (probe depth) and compared with a widely employed ad hoc method. SESSA simulations illustrate the importance of accounting for elastic-scattering events at low photoelectron kinetic energies (<300 eV) where the ad hoc method systematically underestimates the preferential enhancement of anions over cations. Finally, some technical aspects of applying SESSA to liquid interfaces are discussed. [ABSTRACT FROM AUTHOR]

The voltage-gated proton channel Hv1 mediates efflux of protons from the cell. Hv1 integrally contributes to various physiological processes including pH homeostasis and the respiratory burst of phagocytes. Inhibition of Hv1 may provide therapeutic avenues for the treatment of inflammatory diseases, breast cancer, and ischemic brain damage. In this work, we investigate two prototypical Hv1 inhibitors, 2-guanidinobenzimidazole (2GBI), and 5-chloro-2-guanidinobenzimidazole (GBIC), from an experimentally screened class of guanidine derivatives. Both compounds block proton conduction by binding the same site located on the intracellular side of the channel. However, when added to the extracellular medium, the compounds strongly differ in their ability to inhibit proton conduction, suggesting substantial differences in membrane permeability. Here, we compute the potential of mean force for each compound to permeate through the membrane using atomistic molecular dynamics simulations with the adaptive biasing force method. Our results rationalize the putative distinction between these two blockers with respect to their abilities to permeate the cellular membrane. [ABSTRACT FROM AUTHOR]

Hv1 is a voltage-gated proton channel whose main function is to facilitate extrusion of protons from the cell. The development of effective channel blockers for Hv1 can lead to new therapeutics for the treatment of maladies related to Hv1 dysfunction. Although the mechanism of proton permeation in Hv1 remains to be elucidated, a series of small molecules have been discovered to inhibit Hv1. Here, we computed relative binding free energies of a prototypical Hv1 blocker on a model of human Hv1 in an open state. We used alchemical free energy perturbation techniques based on atomistic molecular dynamics simulations. The results support our proposed open state model and shed light on the preferred tautomeric state of the channel blocker. This work lays the groundwork for future studies on adapting the blocker molecule for more effective inhibition of Hv1. [ABSTRACT FROM AUTHOR]

The voltage-gated Hv1 proton channel is a ubiquitous membrane protein that has roles in a variety of cellular processes, including proton extrusion, pH regulation, production of reactive oxygen species, proliferation of cancer cells, and increased brain damage during ischemic stroke. A crystal structure of an Hv1 construct in a putative closed state has been reported, and structural models for the channel open state have been proposed, but a complete characterization of the Hv1 conformational dynamics under an applied membrane potential has been elusive. We report structural models of the Hv1 voltage-sensing domain (VSD), both in a hyperpolarized state and a depolarized state resulting from voltage-dependent conformational changes during a 10-µs-timescale atomistic molecular dynamics simulation in an explicit membrane environment. In response to a depolarizing membrane potential, the S4 helix undergoes an outward displacement, leading to changes in the VSD internal salt-bridge network, resulting in a reshaping of the permeation pathway and a significant increase in hydrogen bond connectivity throughout the channel. The total gating charge displacement associated with this transition is consistent with experimental estimates. Molecular docking calculations confirm the proposed mechanism for the inhibitory action of 2-guanidinobenzimidazole (2GBI) derived from electrophysiological measurements and mutagenesis. The depolarized structural model is also consistent with the formation of a metal bridge between residues located in the core of the VSD. Taken together, our results suggest that these structural models are representative of the closed and open states of the Hv1 channel. [ABSTRACT FROM AUTHOR]

Absorption of terahertz (THz) radiation by aqueous solutions of large solutes reports on the polarization response of their hydration shells. This is because the dipolar relaxation of the solute is dynamically frozen at these frequencies, and most of the solute-induced absorption changes, apart from the expulsion of water, are caused by interfacial water. We propose a model expressing the dipolar response of solutions in terms of a single parameter, the interface dipole moment induced in the interfacial water by electromagnetic radiation. We apply this concept to experimental THz absorption of hydrated sugars, amino acids, and proteins. None of the solutes studied here follow the expectations of dielectric theories, which predict a negative projection of the interface dipole on the external electric field. We find that this prediction is not able to describe the available experimental data, which instead suggests a nearly zero interface dipole for sugars and a more diverse pattern for amino acids. Hydrophobic amino acids, similarly to sugars, give rise to near zero interface dipoles, while strongly hydrophilic ones are best described by a positive projection of the interface dipole on the external field. The sign of the interface dipole is connected to the slope of the absorption coefficient with the solute concentration. A positive slope, implying an increase in the solution polarity relative to water, mirrors results frequently reported for protein solutions. We therefore use molecular dynamics simulations of hydrated glucose and lambda repressor protein to calculate the interface dipole moments of these solutes and the concentration dependence of the THz absorption. The absorption at THz frequencies increases with increasing solute concentration in both cases, implying a higher polarity of the solution compared to bulk water. The structure of the hydration layer, extracted from simulations, is qualitatively similar in both cases, with spatial correlations between the protein and water dipoles extending 4-5 nm into the bulk. The theory makes a testable prediction of the inversion of the positive slope at THz frequencies to a negative slope at lower frequencies of tens to hundreds of GHz. [ABSTRACT FROM AUTHOR]

First-principles molecular dynamics simulations, in which the forces are computed from electronic structure calculations, have great potential to provide unique insight into structure, dynamics, electronic properties, and chemistry of interfacial systems that is not available from empirical force fields. The majority of current first-principles simulations are driven by forces derived from density functional theory with generalized gradient approximations to the exchange-correlation energy, which do not capture dispersion interactions. We have carried out first-principles molecular dynamics simulations of air-water interfaces employing a particular generalized gradient approximation to the exchange-correlation functional (BLYP), with and without empirical dispersion corrections. We assess the utility of the dispersion corrections by comparison of a variety of structural, dynamic, and thermodynamic properties of bulk and interfacial water with experimental data, as well as other first-principles and force field-based simulations. [ABSTRACT FROM AUTHOR]

We report on the development of a modelling consortium for chemistry in indoor environments that connects models over a range of spatial and temporal scales, from molecular to room scales and from sub-nanosecond to days, respectively. Our modeling approaches include molecular dynamics (MD) simulations, kinetic process modeling, gas-phase chemistry modeling, organic aerosol modeling, and computational fluid dynamics (CFD) simulations. These models are applied to investigate ozone reactions with skin and clothing, oxidation of volatile organic compounds and formation of secondary organic aerosols, and mass transport and partitioning of indoor species to surfaces. MD simulations provide molecular pictures of limonene adsorption on SiO2 and ozone interactions with the skin lipid squalene, providing kinetic parameters such as surface accommodation coefficient, desorption lifetime, and bulk diffusivity. These parameters then constrain kinetic process models, which resolve mass transport and chemical reactions in gas and condensed phases for analysis of experimental data. A detailed indoor chemical box model is applied to simulate α-pinene ozonolysis with improved representation of gas–particle partitioning. Application of 2D-volatility basis set reveals that OH-induced aging sometimes drives increases in indoor organic aerosol concentrations, due to organic mass functionalization and enhanced partitioning. CFD simulations show that concentrations of ozone and primary product change near the human surface rapidly, indicating non-uniform spatial distributions from the occupant surface to ambient air, while secondary ozone product is relatively well-mixed throughout the room. This development establishes a framework to integrate different modeling tools and experimental measurements, opening up an avenue for development of comprehensive and integrated models with representations of various chemistry in indoor environments. [ABSTRACT FROM AUTHOR]

Modularly invariant equations of motion are derived that generate the isothermal–isobaric ensemble as their phase space averages. Isotropic volume fluctuations and fully flexible simulation cells as well as a hybrid scheme that naturally combines the two motions are considered. The resulting methods are tested on two problems, a particle in a one-dimensional periodic potential and a spherical model of C60 in the solid/fluid phase. [ABSTRACT FROM AUTHOR]

A new approach is proposed for the determination of transition states and reaction paths for conformational transitions. The method makes use of adiabatic energy surfaces in the space of ‘‘essential’’ degrees of freedom of the molecule. The reduced dimensionality of this space, compared to the full Cartesian space, offers improved computational efficiency and should allow determination of exact reaction paths in systems much larger than those currently amenable to study in Cartesian space. A procedure to obtain reaction paths and free energy profiles in solution is also proposed. The free energy profile along the path in solution is calculated utilizing a free energy perturbation method with constrains and perturbations in internal coordinate space. Applications to a conformational transition of the alanine dipeptide and the folding transition of a model reverse turn in water are presented. For the reverse turn, the sequential flip of dihedral angles reported by Czerminsky and Elber on a similar peptide [J. Chem. Phys. 92, 5580 (1990)] is also observed in the present calculations. The free energy of the extended form of the reverse turn in water is found to be lower than that for the folded conformation by about 3 Kcal/mol, in qualitative accord with previous umbrella sampling calculations. [ABSTRACT FROM AUTHOR]

We have carried out molecular-dynamics simulations with holonomic dihedral angle constraints on two models of n-butane in CCl4 and in water to study the effects of apolar and polar solvents on the gauche-trans equilibrium. We calculated distributions of conformers from the torsional free-energy surfaces for each model of butane in both solvents. For a four-atom model of butane, the gauche-trans equilibrium constant in either solvent is unchanged relative to its gas-phase value. For an all-atom model of butane, the equilibrium population of gauche conformers is increased relative to its gas-phase value by 14% and 31% in CCl4 and water, respectively. The all-atom results are consistent with the idea of solvophobic stabilization of the gauche conformation. We also computed finite-difference temperature derivatives of the free energy to determine its energetic and entropic components. The gauche conformer of the four-atom model is stabilized by entropy and destabilized by energy in CCl4. We find the opposite thermodynamic driving forces for the all-atom model in CCl4. The gauche conformer is favored entropically and opposed energetically for both models in water. This result supports the idea that the butane hydrophobic effect is a manifestation of the hydrophobic interaction. Average interaction energies show that changes in solute–solvent interactions contribute significantly to the trans-gauche internal energy differences in CCl4, while the internal energy differences in water are dominated by changes in the solvent–solvent interactions. Solvent–solute radial distribution functions show that CCl4 packing around the butane molecular is similar to that around other CCl4 molecules, and it is not sensitive to the butane conformation. The water distributions around the butane molecule are very flat, but they show that the water is more disordered around the gauche conformer than the trans. [ABSTRACT FROM AUTHOR]

The method of Ryckaert, Ciccotti, and Berendsen [J. Comp. Phys. 23, 327 (1977)] for integrating the Cartesian equations of motion of a system with holonomic constraints, has been extended to allow the independent constraint of arbitrary internal coordinates. To illustrate this new methodology, and to investigate the effects of dihedral angle constraints on the equilibrium and dynamical properties of macromolecules, we have carried out parallel sets of molecular dynamics simulations and normal mode analyses of a small dipeptide: one without constraints, and one with a single backbone dihedral angle constrained. We find that the averages and the fluctuations of the energies, and of the internal degrees of freedom are not significantly modified by the constraint. However, in the region between 100 and 1400 cm-1 of the normal mode spectrum, the constraint shifts the frequencies of the modes, and modifies their contributions to the spectra of the internal coordinates. Except for the lowest frequency torsional modes, in which anharmonic effects are significant, the behavior of the molecular dynamics power spectra is similar to that of the normal mode spectra. We also illustrate the use of a dihedral angle constraint, in conjunction with a recently developed thermodynamic perturbation method, to calculate the torsional potential of mean force for gas phase n-butane. These results are in good agreement with those obtained in previous studies, and they suggest that the combined internal coordinate constraint/thermodynamic perturbation method is well suited for computing free energy surfaces. As an application of this combined approach, we investigate the role of thermal bond and angle fluctuations on the relative free energies of the three lowest energy conformers of N-methylalanylacetamide. The results indicate that the contribution to the free energy from these fluctuations can be significant, and that care must be taken when models with rigid bonds and angles are... [ABSTRACT FROM AUTHOR]

Dynamic disorder of the lipid bilayer presents a challenge for establishing structure-function relationships in membranous systems. The resulting structural heterogeneity is especially evident for peripheral and spontaneously inserting membrane proteins, which are not constrained by the well-defined transmembrane topology and exert their action in the context of intimate interaction with lipids. Here, we propose a concerted approach combining depth-dependent fluorescence quenching with Molecular Dynamics simulation to decipher dynamic interactions of membrane proteins with the lipid bilayers. We apply this approach to characterize membrane-mediated action of the diphtheria toxin translocation domain. First, we use a combination of the steady-state and time-resolved fluorescence spectroscopy to characterize bilayer penetration of the NBD probe selectively attached to different sites of the protein into membranes containing lipid-attached nitroxyl quenching groups. The constructed quenching profiles are analyzed with the Distribution Analysis methodology allowing for accurate determination of transverse distribution of the probe. The results obtained for 12 NBD-labeled single-Cys mutants are consistent with the so-called Open-Channel topology model. The experimentally determined quenching profiles for labeling sites corresponding to L350, N373, and P378 were used as initial constraints for positioning TH8-9 hairpin into the lipid bilayer for Molecular Dynamics simulation. Finally, we used alchemical free energy calculations to characterize protonation of E362 in soluble translocation domain and membrane-inserted conformation of its TH8-9 fragment. Our results indicate that membrane partitioning of the neutral E362 is more favorable energetically (by ~ 6 kcal/mol), but causes stronger perturbation of the bilayer, than the charged E362. [ABSTRACT FROM AUTHOR]

The constrained molecular-dynamics technique was employed to investigate the transport of a nitrate ion across the water liquid/vapor interface. We developed a nitrate-ion–water polarizable potential that accurately reproduces the solvation properties of the hydrated nitrate ion. The computed free-energy profile for the transfer of the nitrate ion across the air/water interface increases monotonically as the nitrate ion approaches the Gibbs dividing surface from the bulk liquid side. The computed density profiles of 1M KNO3 salt solution indicate that the nitrate and potassium ions are both found below the aqueous interface. Upon analyzing the results, we conclude that the probability of finding the nitrate anion at the aqueous interface is quite small. [ABSTRACT FROM AUTHOR]

It is now well established by numerous experimental and computational studies that the adsorption propensities of inorganic anions conform to the Hofmeister series. The adsorption propensities of inorganic cations, such as the alkali metal cations, have received relatively little attention. Here we use a combination of liquid-jet X-ray photoelectron experiments and molecular dynamics simulations to investigate the behavior of K+ and Li+ ions near the interfaces of their aqueous solutions with halide ions. Both the experiments and the simulations show that Li+ adsorbs to the aqueous solution-vapor interface, while K+ does not. Thus, we provide experimental validation of the "surfactant-like" behavior of Li+ predicted by previous simulation studies. Furthermore, we use our simulations to trace the difference in the adsorption of K+ and Li+ ions to a difference in the resilience of their hydration shells. [ABSTRACT FROM AUTHOR]

The dimeric 44-residue E5 protein of bovine papillomavirus is the smallest known naturally occurring oncoprotein. This transmembrane protein binds to the transmembrane domain (TMD) of the platelet-derived growth factor β receptor (PDGFβR), causing dimerization and activation of the receptor. Here, we use Rosetta membrane modeling and all-atom molecular dynamics simulations in a membrane environment to develop a chemically detailed model of the E5 protein/PDGFβR complex. In this model, an active dimer of the PDGFβR TMD is sandwiched between two dimers of the E5 protein. Biochemical experiments showed that the major PDGFβR TMD complex in mouse cells contains two E5 dimers and that binding the PDGFβR TMD to the E5 protein is necessary and sufficient to recruit both E5 dimers into the complex. These results demonstrate how E5 binding induces receptor dimerization and define a molecular mechanism of receptor activation based on specific interactions between TMDs. [ABSTRACT FROM AUTHOR]

We used targeted molecular dynamics, informed by experimentally determined inter-atomic distances defining the pore region of open and closed states of the KvAP voltage-gated potassium channel, to generate a gating pathway of the pore domain in the absence of the voltage-sensing domains. We then performed umbrella sampling simulations along this pathway to calculate a potential of mean force that describes the free energy landscape connecting the closed and open conformations of the pore domain. The resulting energetic landscape displays three minima, corresponding to stable open, closed, and intermediate conformations with roughly similar stabilities. We found that the extent of hydration of the interior of the pore domain could influence the free energy landscape for pore opening/closing. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Ion spatial distributions at the aqueous–air/vacuum interface are accessible by energy-dependent X-ray photoelectron spectroscopy (XPS). Here we quantify the difference between a flat surface and a cylindrical microjet in terms of the energy-dependent information depth of the XPS experiment and in terms of the simulated photoelectron intensities using solutions of pure water and of 1 mol L−1 NaI as examples. [ABSTRACT FROM AUTHOR]

This special topic contains a diverse collection of 40 articles that span the vast range of subjects that fall under the heading “Ions in Water,” a longstanding mainstay of chemical physics. The investigations reported herein employ state-of-the-art theoretical, computational, and experimental techniques, as well as combinations thereof, to provide new insights into the fundamental aspects of ion solvation and the important roles that ions play in mediating physicochemical processes occurring in solutions and at interfaces in a wide variety of settings relevant to biological, environmental, and technological applications. [ABSTRACT FROM AUTHOR]

The heterotrimeric SecY translocon complex is required for the cotranslational assembly of membrane proteins in bacteria and archaea. The insertion of transmembrane (TM) segments during nascent-chain passage through the translocon is generally viewed as a simple partitioning process between the water-filled translocon and membrane lipid bilayer, suggesting that partitioning is driven by the hydrophobic effect. Indeed, the apparent free energy of partitioning of unnatural aliphatic amino acids on TM segments is proportional to accessible surface area, which is a hallmark of the hydrophobic effect [Öjemalm K, et al. (2011) Proc Natl Acad Sci USA 108(31):E359-E364]. However, the apparent partitioning solvation parameter is less than one-half the value expected for simple bulk partitioning, suggesting that the water in the translocon departs from bulk behavior. To examine the state of water in a SecY translocon complex embedded in a lipid bilayer, we carried out all-atom molecular-dynamics simulations of the Pyrococcus furiosus SecYE, which was determined to be in a "primed" open state [Egea PF, Stroud RM (2010) Proc Natl Acad Sci USA 107(40):17182-17187]. Remarkably, SecYE remained in this state throughout our 450-ns simulation. Water molecules within SecY exhibited anomalous diffusion, had highly retarded rotational dynamics, and aligned their dipoles along the SecY trans-membrane axis. The translocon is therefore not a simple water-filled pore, which raises the question of how anomalous water behavior affects the mechanism of translocon function and, more generally, the partitioning of hydrophobic molecules. Because large water-filled cavities are found in many membrane proteins, our findings may have broader implications. [ABSTRACT FROM AUTHOR]

The paired helical filaments (PHF) formed by the intrinsically disordered human protein tau are one of the pathological hallmarks of Alzheimer disease. PHF are fibers of amyloid nature that are composed of a rigid core and an unstructured fuzzy coat. The mechanisms of fiber formation, in particular the role that hydration water might play, remain poorly understood.We combined protein deuteration, neutron scattering, and all-atom molecular dynamics simulations to study the dynamics of hydration water at the surface of fibers formed by the full-length human protein htau40. In comparison with monomeric tau, hydration water on the surface of tau fibers is more mobile, as evidenced by an increased fraction of translationally diffusing water molecules, a higher diffusion coefficient, and increased mean-squared displacements in neutron scattering experiments. Fibers formed by the hexapeptide 306VQIVYK311 were taken as a model for the tau fiber core and studied by molecular dynamics simulations, revealing that hydration water dynamics around the core domain is significantly reduced after fiber formation. Thus, an increase in water dynamics around the fuzzy coat is proposed to be at the origin of the experimentally observed increase in hydration water dynamics around the entire tau fiber. The observed increase in hydration water dynamics is suggested to promote fiber formation through entropic effects. Detection of the enhanced hydrationwater mobility around tau fibers is conjectured to potentially contribute to the early diagnosis of Alzheimer patients by diffusion MRI. [ABSTRACT FROM AUTHOR]

The major removal processes for gaseous nitric acid (HNO3) in the atmosphere are dry and wet deposition onto various surfaces. The surface in the boundary layer is often covered with organic films, but the interaction of gaseous HNO3 with them is not well understood. To better understand the factors controlling the uptake of gaseous nitric acid and its dissociation in organic films, studies were carried out using single component and mixtures of C8 and C18 alkyl self-assembled monolayers (SAMs) attached to a germanium (Ge) attenuated total reflectance (ATR) crystal upon which a thin layer of SiOx had been deposited. For comparison, diffuse reflectance infrared Fourier transform spectrometry (DRIFTS) studies were also carried out using a C18 SAM attached to the native oxide layer on the surface of silicon powder. These studies show that the alkyl chain length and order/disorder of the SAMs does not significantly affect the uptake or dissociation/recombination of molecular HNO3. Thus, independent of the nature of the SAM, molecular HNO3 is observed up to 70–90% relative humidity. After dissociation, molecular HNO3 is regenerated on all SAM surfaces when water is removed. Results of molecular dynamics simulations are consistent with experiments and show that defects and pores on the surfaces control the uptake, dissociation and recombination of molecular HNO3. Organic films on surfaces in the boundary layer will certainly be more irregular and less ordered than SAMs studied here, therefore undissociated HNO3 may be present on surfaces in the boundary layer to a greater extent than previously thought. The combination of this observation with the results of recent studies showing enhanced photolysis of nitric acid on surfaces suggests that renoxification of deposited nitric acid may need to be taken into account in atmospheric models. [ABSTRACT FROM AUTHOR]

Nitrate and halide ions coexist in particles generated in marine regions, around alkaline dry lakes, and in the Arctic snowpack. Although the photochemistry of nitrate ions in bulk aqueous solution is well known, there is recent evidence that it may be more efficient at liquid–gas interfaces, and that the presence of other ions in solution may enhance interfacial reactivity. This study examines the 311 nm photolysis of thin aqueous films of ternary halide–nitrate salt mixtures (NaCl–NaBr–NaNO3) deposited on the walls of a Teflon chamber at 298 K. The films were generated by nebulizing aqueous 0.25 M NaNO3 solutions which had NaCl and NaBr added to vary the mole fraction of halide ions. Molar ratios of chloride to bromide ions were chosen to be 0.25, 1.0, or 4.0. The subsequent generation of gas phase NO2 and reactive halogen gases (Br2, BrCl and Cl2) were monitored with time. The rate of gas phase NO2 formation was shown to be enhanced by the addition of the halide ions to thin films containing only aqueous NaNO3. At [Cl−]/[Br−] ≤ 1.0, the NO2 enhancement was similar to that observed for binary NaBr–NaNO3 mixtures, while with excess chloride NO2 enhancement was similar to that observed for binary NaCl–NaNO3 mixtures. Molecular dynamics simulations predict that the halide ions draw nitrate ions closer to the interface where a less complete solvent shell allows more efficient escape of NO2 to the gas phase, and that bromide ions are more effective in bringing nitrate ions closer to the surface. The combination of theory and experiments suggests that under atmospheric conditions where nitrate ion photochemistry plays a role, the impact of other species such as halide ions should be taken into account in predicting the impacts of nitrate ion photochemistry. [ABSTRACT FROM AUTHOR]

Calmodulin (CaM) is a universal regulatory protein that communicates the presence of calcium to its molecular targets and correspondingly modulates their function. This key signaling protein is important for controlling the activity of hundreds of membrane channels and transporters. However, understanding of the structural mechanisms driving CaM regulation of full-length membrane proteins has remained elusive. In this study, we determined the pseudoatomic structure of full-length mammalian aquaporin-0 (AQP0, Bos taurus) in complex with CaM, using EM to elucidate how this signaling protein modulates water-channel function. Molecular dynamics and functional mutation studies reveal how CaM binding inhibits AQP0 water permeability by allosterically closing the cytoplasmic gate of AQP0. Our mechanistic model provides new insight, only possible in the context of the fully assembled channel, into how CaM regulates multimeric channels by facilitating cooperativity between adjacent subunits. [ABSTRACT FROM AUTHOR]

Chemistry occurring at or near the surface of aqueous droplets and thin films in the atmosphere influences air quality and climate. Molecular dy-namics simulations are becoming increasingly useful for gaining atomic-scale insight into the structure and reactivity of aqueous interfaces in the atmosphere. Here we review simulation studies of atmospherically relevant aqueous liquid-air interfaces, with an emphasis on ions that play important roles in the chemistry of atmospheric aerosols. In addition to surveying re-sults from simulation studies, we discuss challenges to the refinement and experimental validation of the methodology for simulating ion adsorption to the air-water interface and recent advances in elucidating the driving forces for adsorption. We also review the recent development of a dielectric con-tinuum theory capable of reproducing simulation and experimental data on ion behavior at aqueous interfaces. [ABSTRACT FROM AUTHOR]

Several laboratories have carried out molecular dynamics (MD) simulations of arginine interactions with lipid bilayers and found that the energetic cost of placing arginine in lipid bilayers is an order of magnitude greater than observed in molecular biology experiments in which Arg-containing transmembrane helices are inserted across the endoplasmic reticulum membrane by the Sec61 translocon. We attempt here to reconcile the results of the two approaches. We first present MD simulations of guanidinium groups alone in lipid bilayers, and then, to mimic the molecular biology experiments, we present simulations of hydrophobic helices containing single Arg residues at different positions along the helix. We discuss the simulation results in the context of molecular biology results and show that the energetic discrepancy is reduced, but not eliminated, by considering free energy differences between Arg at the interface and at the center of the model helices. The reduction occurs because Arg snorkeling to the interface prevents Arg from residing in the bilayer center where the energetic cost of desolvation is highest. We then show that the problem with MD simulations is that they measure water-to-bilayer free energies, whereas the molecular biology experiments measure the energetics of partitioning from translocon to bilayer, which raises the fundamental question of the relationship between water-to-bilayer and water-to-translocon partitioning. We present two thermodynamic scenarios as a foundation for reconciliation of the simulation and molecular biology results. The simplest scenario is that translocon-to-bilayer partitioning is independent of water-to-bilayer partitioning; there is no thermodynamic cycle connecting the two paths. [ABSTRACT FROM AUTHOR]

Inorganic salts in marine aerosols play an active role in atmospheric chemistry, particularly in coastal urban regions. The study of the interactions of these ions with water molecules at the aqueous surface helps to elucidate the role of inorganic cations and anions in atmospheric processes. We present surface vibrational sum frequency generation (SFG) spectroscopic and molecular dynamics (MD) studies of aqueous MgCl2 surfaces as models of marine aerosol. Spectroscopy results reveal that the disturbance of the hydrogen bonding environment of the air/aqueous interface is dependent on the MgCl2 concentration. At low concentrations (<1 M) minor changes are observed. At concentrations above 1 M the hydrogen bonding environment is highly perturbed. The 2.1 M intermediate concentration solution shows the largest SFG response relative to the other solutions including concentrations as high as 4.7 M. The enhancement of SFG signal observed for the 2.1 M solution is attributed to a larger SFG-active interracial region and more strongly oriented water molecules relative to other concentrations. MD simulations reveal concentration dependent compression of stratified layers of ions and water orientation differences at higher concentrations. SFG and MD studies of the dangling OH of the surface water reveal that the topmost water layer is affected structurally at high concentrations (>3.1 M). Finally, the MgCl2 concentration effect on a fatty acid coated aqueous surface was investigated and SFG spectra reveal that deprotonation of the carboxylic acid of atmospherically relevant palmitic acid (PA) is accompanied by binding of the Mg2+ to the PA headgroup. [ABSTRACT FROM AUTHOR]

Despite the growing number of atomic-resolution membrane protein structures, direct structural information about proteins in their native membrane environment is scarce. This problem is particularly relevant in the case of the highly charged S1–S4 voltage-sensing domains responsible for nerve impulses, where interactions with the lipid bilayer are critical for the function of voltage-activated ion channels. Here we use neutron diffraction, solid-state nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulations to investigate the structure and hydration of bilayer membranes containing S1–S4 voltage-sensing domains. Our results show that voltage sensors adopt transmembrane orientations and cause a modest reshaping of the surrounding lipid bilayer, and that water molecules intimately interact with the protein within the membrane. These structural findings indicate that voltage sensors have evolved to interact with the lipid membrane while keeping energetic and structural perturbations to a minimum, and that water penetrates the membrane, to hydrate charged residues and shape the transmembrane electric field. [ABSTRACT FROM AUTHOR]

The insertion efficiency of transmembrane (TM) helices by the Sec61 translocon depends on helix amino acid composition, the positions of the amino acids within the helix, and helix length. We have used an in vitro expression system to examine systematically the insertion efficiency of short polyleucine segments (Ln, n = 4 … 12) flanked at either end by 4-residue sequences of the form XXPX-Ln-XPXX with X = G, N, D, or K. Except for X = K, insertion efficiency (p) is <10% for n < 8, but rises steeply to 100% for n = 12. For X = K, p is already close to 100% for n = 10. A similar pattern is observed for synthetic peptides incorporated into oriented phospholipid bilayer arrays, consistent with the idea that recognition of TM segments by the translocon critically involves physical partitioning of nascent peptide chains into the lipid bilayer. Molecular dynamics simulations suggest that insertion efficiency is determined primarily by the energetic cost of distorting the bilayer in the vicinity of the TM helix. Very short lysine-flanked leucine segments can reduce the energetic cost by extensive hydrogen bonding with water and lipid phosphate groups (snorkeling) and by partial unfolding. [ABSTRACT FROM AUTHOR]

Voltage-sensitive ion channels open and close in response to changes in transmembrane (TM) potential caused by the motion of the S4 voltage sensors. These sensors are α-helices that include four or more positively charged amino acids, most commonly arginine. The so-called paddle model, based on the high-resolution structure of the KvAP K+ channel [Jiang, et al. (2003) Nature 423, 33-41], posits that the S4 sensors move within the membrane bilayer in response to TM voltage changes. Direct exposure of S4 sensors to lipid is contrary to the classical expectation that the dielectric contrast between the membrane hydrocarbon core and water presents an insurmountable energetic penalty to burial of electric charges. Nevertheless, recent experiments have shown that a helix with the sequence of KvAP S4 can be inserted across the endoplasmic reticulum membrane. To reconcile this result with the classical energetics argument we have carried out a molecular dynamics simulation of an isolated TM S4 helix in a lipid bilayer. The simulation reveals a stabilizing hydrogen-bonded network of water and lipid phosphates around the arginines that reduces the effective thickness of the bilayer hydrocarbon core to ≈10 Å in the vicinity of the helix. It suggests that bilayer phospholipids can adapt locally to strongly perturbing protein elements, causing the phospholipids to become a structural extension of the protein. [ABSTRACT FROM AUTHOR]

The anti-apoptotic protein Bcl-xL regulates apoptosis by preventing the permeation of the mitochondrial outer membrane by pro-apoptotic pore-forming proteins, which release apoptotic factors into the cytosol that ultimately lead to cell death. Two different membrane-integrated Bcl-xL constructs have been identified: a membrane-anchored and a membrane-inserted conformation. Here, we use molecular dynamics simulations to study the effect of the mitochondrial specific lipid cardiolipin and the protein protonation state on the conformational dynamics of membrane-anchored Bcl-xL. The analysis reveals that the protonation state of the protein and cardiolipin content of the membrane modulate the orientation of the soluble head region (helices α1 through α7) and hence the exposure of its BH3-binding groove, which is required for its interaction with pro-apoptotic proteins. [ABSTRACT FROM AUTHOR]

Explicit reversible integrators, suitable for use in large-scale computer simulations, are derived for extended systems generating the canonical and isothermal-isobaric ensembles. The new methods are compared with the standard implicit (iterative) integrators on some illustrative example problems. In addition, modification of the proposed algorithms for multiple time step integration is outlined. [ABSTRACT FROM AUTHOR]

Work from our laboratory using molecular dynamics applied to the study of peptide/protein folding dynam ics and thermodynamics in aqueous solution, and the exploration and development of molecular solvent in teraction models including electronic polarizability is described. The basic computational techniques we have used in developing algorithms for vector/parallel, shared memory, multiple instruction, multiple data (MIMD) and massively parallel single instruction, multi ple data (SIMD) architectures are discussed in the con text of these application areas. The technique we have used to parallelize the molecular dynamics/molecular mechanics code CHARMM is detailed, with special fo cus given to the performance issues faced in develop ing algorithms for the CRAY Y-MP. New developments of a molecular dynamics kernel for simulation of elec tronically polarizable solvent systems using a parallel- extended Fortran language (Fortran-9X) on the mas sively parallel Connection Machine (CM-2) are out lined. We provide examples of applications using both of these platforms and discuss the development of software for such simulations in a heterogeneous com putational environment. [ABSTRACT FROM PUBLISHER]

We performed molecular dynamics simulations using both polarizable and non-polarizable force fields to study the adsorption of iodide to the air-water interface. A novel aspect of our analysis is that the progress of ion adsorption is measured as the distance from the instantaneous interface, which is defined by a coarse-graining scheme proposed recently by Willard and Chandler ['Instantaneous liquid interfaces,' J. Phys. Chem. B 114, 1954-1958 (2010)]. Referring structural and thermodynamic quantities to the instantaneous interface unmasks molecular-scale details that are obscured by thermal fluctuations when the same quantities are referred to an average measure of the position of the interface, such as the Gibbs dividing surface. Our results suggest that an ion adsorbed at the interface resides primarily in the topmost water layer, and the interfacial location of the ion is favored by enthalpy and opposed by entropy. [ABSTRACT FROM AUTHOR]

The Symposium 'Frontiers in membrane and membrane protein biophysics: experiments and theory', held this year at the University of California, Irvine (August 19-20), celebrated the 70th Birthday of Stephen H. White by bringing together distinguished experimentalists and theoreticians to discuss the state of the art and future challenges in the field of membrane and membrane protein biophysics. The meeting and this special issue highlight the highly interdisciplinary nature of membrane and membrane protein biophysics, and the tremendous contributions that S. H. White and his lab have brought to the field. [ABSTRACT FROM AUTHOR]

We report a MD simulation study of the behavior of the boson peak of a globular protein in realistic powder environments corresponding to conditions of neutron scattering studies (hydrated at 150 K, dry at 150 K, and dry at 300 K). The temperature and hydration dependence of the boson peak, an excess of inelastic scattering intensity over the harmonic background at low frequency, are in excellent agreement with neutron scattering data on powder samples of several proteins. To gain further insight into the nature of boson peak, and its relation to hydration water, we have decomposed the inelastic spectrum into contributions from the protein backbone, nonpolar side chains in the interior of the protein, and polar side chains exposed to the solvent. We find that the boson peak arises from motions distributed throughout the protein, regardless of the conditions of temperature and hydration. Furthermore, the relative contribution from each part of the protein considered shows a similar temperature and hydration dependence. This demonstrates that the damping of the boson peak upon hydration is not solely due to the damping of the water-coupled motion of exposed polar side chains, but rather propagates through the whole protein. © 2001 American Institute of Physics. [ABSTRACT FROM AUTHOR]

The structure and dynamics of Cl[sup -](H[sub 2]O)[sub 6] has been studied by ab initio molecular dynamics using the Car-Parrinello approach, and compared to results of ab initio quantum chemical calculations, molecular dynamics based on both polarizable and nonpolarizable empirical potentials, and vibrational spectroscopy. The electronic structure methodology (density functional theory with the gradient-corrected BLYP exchange-correlation functional) used in the Car-Parrinello dynamics has been shown to give good agreement with second-order Møller-Plesset results for the structures and energies of Cl[sup -](H[sub 2]O)[sub n], n=1-4, clusters. The configurational sampling during the 5 ps ab initio molecular dynamics simulation at 250 K was sufficient to demonstrate that the chloride anion preferred a location on the surface of the cluster which was significantly extended compared to the minimum energy geometry. The structure of the cluster predicted by the polarizable force field simulation is in agreement with the ab initio simulation, while the nonpolarizable force field calculation was in qualitative disagreement, predicting an interior location for the anion. The time evolution of the electronic structure during the ab initio simulation was analyzed in terms of maximally localized orbitals (Wannier functions). Calculation of the dipole moments from the centers of the Wannier orbitals revealed that the chloride anion is significantly polarized, and that the extent of water polarization depends on location in the cluster, thus underscoring the importance of electronic polarization in halogen ion solvation. The infrared absorption spectrum was computed from the dipole-dipole correlation function, including both nuclear and electronic contributions. Aside from a systematic redshift by 3%-5% in the frequencies, the computed spectrum was in quantitative agreement with vibrational predissociation data on Cl[sup -](H[sub 2]O)[sub 5]. Our analysis sugges... [ABSTRACT FROM AUTHOR]

Multiphase reactions of ozone with human skin oils impact indoor air quality by depleting ozone and forming semi-volatile organic compounds, which can be respiratory and skin irritants. Here we demonstrate the impact of clothing on indoor air composition and human exposure by integrating indoor chemistry modeling over a wide range of different spatial and temporal scales. Constrained by molecular dynamics simulations that provide key kinetic parameters, the kinetic model reproduces experimental measurements and predicts that squalene could persist in clothing for several hours to over a day depending on ozone concentrations. Soiled clothing protects skin from ozone exposure even with high concentrations, but can enhance concentrations of oxidation products to a ppb level depending on air exchange rates. Computational fluid dynamics simulations reveal that primary products have ~1.6–2.0 times higher concentrations in the breathing zone than in bulk room air, while secondary products are distributed more uniformly throughout a room. Reactions of ozone with human skin oils impact indoor air quality by depleting ozone and forming semi-volatile organic compounds. Here, the authors examine the impact of clothing on indoor air composition and human exposure by integrating indoor chemistry modeling over a range of spatial and temporal scales. [ABSTRACT FROM AUTHOR]