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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]

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]

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]

Using molecular dynamics simulations, we analyze collective vibrations in the hydration water of a small globular protein. We develop tools that allow spatial resolution of correlated protein and water motion, and use them to reveal correlated vibrations that extend up to 10 Å from the protein surface at far-infrared/THz frequencies that are sensitive to the chemical properties of the protein surface. Our results provide the first detailed description of long-range effects on protein hydration water dynamics and highlight the differences between single particle and collective dynamics, which are relevant in interpreting experimental observations. [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]

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]

The article discusses the role of aqueous ion-containing interfaces in a plethora of physical, chemical, atmospheric and biological processes. Ions at the air/water interface are important for atmospheric chemistry involving ocean surfaces and seawater aerosols. Ion specificity plays an important role for interactions between colloid particles in electrolytes and for the stability of aggregates of amphiphilic species.

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]

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 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]

The article analyzes the contribution of methyl groups to purple membrane (PM) dynamics as measured by elastic incoherent neutron scattering (EINS), using isotope labeling and molecular dynamics (MD) simulations. A single membrane protein, bacteriorhodopsin (BR) and various lipid species form PM. The dynamics of a non-methyl-containing side chain, lysine, is measured in BR. A completely deuterated PM in which lysine residues are hydrogenated is studied. The lysine side chain is representative of non-methyl-containing moieties in the protein.

The article presents a study about the properties of salt solutions and its specific ion effects. Here, researchers prove why lite salt tastes different from ordinary table salt. One important and previously neglected source of ion specificity is the ionic dispersion potential that acts between each ion and the protein. Furthermore, the researchers demonstrate that once ionic dispersion potentials are included in the theory these results can quantitatively be reinterpreted in terms of a highly specific surface hydrogen ion concentration.

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]

Organized as bilayers, phospholipids are the fundamental building blocks of cellular membranes and determine many of their biological functions. Interactions between the two leaflets of the bilayer (interleaflet coupling) have been implicated in the passage of information through membranes. However, physically, the meaning of interleaflet coupling is ill defined and lacks a structural basis. Using all-atom molecular dynamics simulations of fluid phospholipid bilayers of five different lipids with differing degrees of acyl-chain asymmetry, we have examined interleaflet mixing to gain insights into coupling. Reasoning that the transbilayer distribution of terminal methyl groups is an appropriate measure of interleaflet mixing, we calculated the transbilayer distributions of the acyl chain terminal methyl groups for five lipids: dioleoylphosphatidylcholine (DOPC), palmitoyloleoylphosphatidylcholine (POPC), stearoyloleoylphosphatidylcholine (SOPC), oleoylmyristoylphosphatidylcholine (OMPC), and dimyristoylphosphatidylcholine (DMPC). We observed in all cases very strong mixing across the bilayer midplane that diminished somewhat with increasing acyl-chain ordering defined by methylene order parameters. A hallmark of the interleaflet coupling idea is complementarity, which postulates that lipids with short alkyl chains in one leaflet will preferentially associate with lipids with long alkyl chains in the other leaflet. Our results suggest a much more complicated picture for thermally disordered bilayers that we call distributed complementarity, as measured by the difference in the peak positions of the sn -1 and sn -2 methyl distributions in the same leaflet. [ABSTRACT FROM AUTHOR]

Translocation of negatively charged ions across cell membranes by ion pumps raises the question as to how protein interactions control the location and dynamics of the ion. Here we address this question by performing extensive molecular dynamics simulations of wild type and mutant halorhodopsin, a seven-helical transmembrane protein that translocates chloride ions upon light absorption. We find that inter-helical hydrogen bonds mediated by a key arginine group largely govern the dynamics of the protein and water groups coordinating the chloride ion. [ABSTRACT FROM AUTHOR]

Thepropensities of the water self-ions, H3O+andOH–, for the air–water interface haveimplications for interfacial acid–base chemistry. Despite numerousexperimental and computational studies, no consensus has been reachedon the question of whether or not H3O+and/orOH–prefer to be at the water surface or in thebulk. Here we report a molecular dynamics simulation study of thebulk vs interfacial behavior of H3O+and OH–that employs forces derived from density functionaltheory with a generalized gradient approximation exchange-correlationfunctional (specifically, BLYP) and empirical dispersion corrections.We computed the potential of mean force (PMF) for H3O+as a function of the position of the ion in the vicinityof an air–water interface. The PMF suggests that H3O+has equal propensity for the interface and the bulk.We compare the PMF for H3O+to our previouslycomputed PMF for OH–adsorption, which containsa shallow minimum at the interface, and we explore how differencesin solvation of each ion at the interface vs in the bulk are connectedwith interfacial propensity. We find that the solvation shell of H3O+is only slightly dependent on its position inthe water slab, while OH–partially desolvates asit approaches the interface, and we examine how this difference insolvation behavior is manifested in the electronic structure and chemistryof the two ions. [ABSTRACT FROM AUTHOR]

The accommodation of water vapor at the air/water interface is studied using classical molecular dynamics computer simulations. From 250 initial conditions of a gas phase water molecule approaching the surface of liquid water with a thermal impact velocity, the thermal and mass accommodation coefficients are determined to be 1.0 and 0.99, respectively, at 300 K. When the approaching water molecule is 5 Å above the liquid, it is accelerated towards the surface, which is followed by a slight rotational excitation upon impact. Within 4 ps of striking the surface, the total kinetic energy is equilibrated and the equilibrium number of water molecules in the first and second solvent shells is obtained. [Copyright &y& Elsevier]

The dynamics of α-lactalbumin in the native and molten globule states in solution was investigated using quasielastic neutron scattering and molecular dynamics simulations. We generated 2 nanosecond molecular dynamics trajectories at 300 K of α-lactalbumin solvated in a water box in the native state, and a putative member of the ensemble of conformations of the molten globule state generated by simulation at high temperature. Overall the agreement between the measured and calculated dynamical structure factors is good. Preliminary analysis of the simulated dynamics of the molten globule state revealed a strong heterogeneity of motions along the protein backbone, with larger amplitudes in the regions of the protein that unfold, mainly the β-sheet region. The results presented here demonstrate the utility of using a combination of neutron scattering measurements and molecular dynamics simulations to characterize and quantify, in a sequence-specific fashion, the differences in dynamics between the native and partially folded states of proteins on the time scale (∼100 ps) and length scale (a few to tens of A˚) probed by current neutron spectrometers. [Copyright &y& Elsevier]

Polarizability of the sulfate dianion solvated in water clusters and in an extended water slab is investigated by a combination of ab initio calculations and classical and Car–Parrinello molecular dynamics. Quantum chemistry calculations at the MP2/aug-cc-pvdz level are performed for structures obtained from molecular dynamics simulations replacing water oxygens and hydrogens by fractional point charges. Sulfate polarizability in bulk water amounts to roughly 7 A˚3. Despite this large value SO42− clearly prefers interior over surface solvation, in accord with previous experimental evidence for large aqueous clusters. [Copyright &y& Elsevier]

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]

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]

The article covers the progress in the interpretation of the structure and chemistry at aqueous interfaces. The focus is strongly on investigations with molecular resolution which provide detailed and accurate information about the structure of the interface. Progress in molecular level understanding of aqueous interfaces is a good example of fruitful feedback between experiments, theory, and simulations.

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]

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]

Abstract Aquaporin 0 (AQP0) is essential for eye lens homeostasis as is regulation of its water permeability by Ca2+, which occurs through interactions with calmodulin (CaM), but the underlying molecular mechanisms are not well understood. Here, we use molecular dynamics (MD) simulations on the microsecond timescale under an osmotic gradient to explicitly model water permeation through the AQP0 channel. To identify any structural features that are specific to water permeation through AQP0, we also performed simulations of aquaporin 1 (AQP1) and a pure mixed lipid bilayer under the same conditions. The relative single-channel water osmotic permeability coefficients (p f) calculated from all of our simulations are in reasonable agreement with experiment. Our simulations allowed us to characterize the dynamics of the key structural elements that modulate the diffusion of water single-files through the AQP0 and AQP1 pores. We find that CaM binding influences the collective dynamics of the whole AQP0 tetramer, promoting the closing of both the extracellular and intracellular gates by inducing cooperativity between neighboring subunits. Graphical abstract Unlabelled Image Highlights • Open-closed exchange rates in AQP0 and AQP1 correlate well with permeation rates. • CaM binding to AQP0 promotes the closing of the channel at both CS-I and CS-II. • AQP0 water permeability reduction upon CaM binding is cooperative. [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]

Specific ion effects of the large halide anions have been shown to moderate anion adsorption to the air-water interface (AWI), but little quantitative attention has been paid to the behavior of alkali cations. Here we investigate the concentration and local distribution of sodium (Na+) at the AWI in dilute (<1 M) aqueous solutions of NaCl, NaBr, and NaI using a combination of molecular dynamics (MD) and SESSA simulations, and liquid jet ambient pressure photoelectron spectroscopy measurements. We use SESSA to simulate Na 2p photoelectron intensities on the basis of the atom density profiles obtained from MD simulations, and we compare the simulation results with photoelectron spectroscopy experiments to evaluate the performance of a nonpolarizable force field model versus that of an induced dipole polarizable one. Our results show that the nonpolarizable force model developed by Horinek and co-workers (Chem. Phys. Lett. 2009, 479, 173-183) accurately predicts the local concentration and distribution of Na+ near the AWI for all three electrolytes, whereas the polarizable model does not. To our knowledge, this is the first interface-specific spectroscopic validation of a MD force field. The molecular origins of the unique Na+ distributions for the three electrolytes are analyzed on the basis of electrostatic arguments, and shown to arise from an indirect anion effect wherein the identity of the anion affects the strength of the attractive Na+-H2O electrostatic interaction. Finally, we use the photoelectron spectroscopy results to constrain the range of inelastic mean free paths (IMFPs) for the three electrolyte solutions used in the SESSA simulations that are able to reproduce the experimental intensities. Our results suggest that earlier estimates of IMFPs for aqueous solutions are likely too high. [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 ion distribution and ion pairing properties of Mg2+, SO42-, NO3-, and Cl- in the interfacial region of MgSO4, Mg(NO3)2, and MgCl2 solutions were investigated using vibrational sum frequency generation (VSFG) spectroscopy and molecular dynamics (MD) simulations. An electric field reversal relative to Mg(NO3)2 and MgCl2 solutions is observed at the interface of a MgSO4 solution. We show that, although magnesium cations are expected to have preference for bulk solvation, solvent-shared ion pairs (SIPs) exist in the interfacial region in which Mg2+ cations are closer to the solution surface than sulfate anions. While interfacial SIPs are few, they dominate the electric field effect observed. Thus, SIPs play a significant role in determining the electric field direction and magnitude at the air-aqueous interface. In addition to impact on the fundamental understanding of aqueous surfaces and interfacial ion-ion interactions, these findings have implications for atmospheric aerosol chemistry and thundercloud electrification. [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]

Voltage-sensing domains (VSDs) sense changes in the membrane electrostatic potential and, through conformational changes, regulate a specific function. The VSDs of wild-type voltage-dependent K+, Na+, and Ca2+ channels do not conduct ions, but they can become ion-permeable through pathological mutations in the VSD. Relatively little is known about the underlying mechanisms of conduction through VSDs. The most detailed studies have been performed on Shaker K+ channel variants in which ion conduction through the VSD is manifested in electrophysiology experiments as a voltage-dependent inward current, the so-called omega current, which appears when the VSDs are in their resting state conformation. Only monovalent cations appear to permeate the Shaker VSD via a pathway that is believed to be, at least in part, the same as that followed by the S4 basic side chains during voltage-dependent activation. We performed Ās-time scale atomistic molecular dynamics simulations of a cation-conducting variant of the Shaker VSD under applied electric fields in an experimentally validated resting-state conformation, embedded in a lipid bilayer surrounded by solutions containing guanidinium chloride or potassium chloride. Our simulations provide insights into the Shaker VSD permeation pathway, the protein-ion interactions that control permeation kinetics, and the mechanism of voltage-dependent activation of voltage-gated ion channels. [ABSTRACT FROM AUTHOR]

Aquaporin 0 (AQP0), the major intrinsic protein of the eye lens, plays a vital role in maintaining lens clarity by facilitating the transport of water across lens fiber cell membranes. AQP0 reduces its osmotic water permeability constant (Pf) in response to increases in the external calcium concentration, an effect that is mediated by an interaction with the calcium-binding messenger protein, calmodulin (CaM), and phosphorylation of the CaM-binding site abolishes calcium sensitivity. Despite recent structural characterization of the AQP0-CaM complex, the mechanism by which CaM modulates AQP0 remains poorly understood. By combining atomistic molecular dynamics simulations and oocyte permeability assays, we conclude that serine phosphorylation of AQP0 does not inhibit CaM binding to the whole AQP0 protein. Instead, AQP0 phosphorylation alters calcium sensitivity by modifying the AQP0-CaM interaction interface, particularly at an arginine-rich loop that connects the fourth and fifth transmembrane helices. This previously unexplored loop, which sits outside of the canonical CaM-binding site on the AQP0 cytosolic face, mechanically couples CaM to the pore-gating residues of the second constriction site. We show that this allosteric loop is vital for CaM regulation of the channels, facilitating cooperativity between adjacent subunits and regulating factors such as serine phosphorylation. Similar allosteric interactions may also mediate CaM modulation of the properties of other CaM-regulated proteins. [ABSTRACT FROM AUTHOR]

We present a novel multi-conformation Monte Carlo simulation method that enables the modeling of protein-protein interactions and aggregation in crowded protein solutions. This approach is relevant to a molecular-scale description of realistic biological environments, including the cytoplasm and the extracellular matrix, which are characterized by high concentrations of biomolecular solutes (e.g., 300-400 mg/mL for proteins and nucleic acids in the cytoplasm of Escherichia coli). Simulation of such environments necessitates the inclusion of a large number of protein molecules. Therefore, computationally inexpensive methods, such as rigid-body Brownian dynamics (BD) or Monte Carlo simulations, can be particularly useful. However, as we demonstrate herein, the rigid-body representation typically employed in simulations of many-protein systems gives rise to certain artifacts in protein-protein interactions. Our approach allows us to incorporate molecular flexibility in Monte Carlo simulations at low computational cost, thereby eliminating ambiguities arising from structure selection in rigid-body simulations. We benchmark and validate the methodology using simulations of hen egg white lysozyme in solution, a well-studied system for which extensive experimental data, including osmotic second virial coefficients, small-angle scattering structure factors, and multiple structures determined by X-ray and neutron crystallography and solution NMR, as well as rigid-body BD simulation results, are available for comparison. [ABSTRACT FROM AUTHOR]

The article presents information on methyl group dynamics as a probe of the protein dynamical transition. As the temperature is raised above 2OO K, hydrated proteins undergo a change in dynamics, the so-called dynamical transition, from glasslike, in which the motion is primarily vibrational, to liquid-like, in which transitions between taxonomic substates are possible. When a wide range of T (50-300 K) spanning the transition is considered the whole distribution of methyl group fluctuations in the hydrated protein (crystal) shifts to lower mobility.

Background The objective of this study was to determine whether the cataract-related G18V variant of human γ S-crystallin has increased exposure of hydrophobic residues that could explain its aggregation propensity and/or recognition by α B-crystallin. Methods We used an ANS fluorescence assay and NMR chemical shift perturbation to experimentally probe exposed hydrophobic surfaces. These results were compared to flexible docking simulations of ANS molecules to the proteins, starting with the solution-state NMR structures of γ S-WT and γ S-G18V. Results γ S-G18V exhibits increased ANS fluorescence, suggesting increased exposed hydrophobic surface area. The specific residues involved in ANS binding were mapped by NMR chemical shift perturbation assays, revealing ANS binding sites in γ S-G18V that are not present in γ S-WT. Molecular docking predicts three binding sites that are specific to γ S-G18V corresponding to the exposure of a hydrophobic cavity located at the interdomain interface, as well as two hydrophobic patches near a disordered loop containing solvent-exposed cysteines, all but one of which is buried in γ S-WT. Conclusions Although both proteins display non-specific binding, more residues are involved in ANS binding to γ S-G18V, and the affected residues are localized in the N-terminal domain and the nearby interdomain interface, proximal to the mutation site. General significance Characterization of changes in exposed hydrophobic surface area between wild-type and variant proteins can help elucidate the mechanisms of aggregation propensity and chaperone recognition, presented here in the context of cataract formation. Experimental data and simulations provide complementary views of the interactions between proteins and the small molecule probes commonly used to study aggregation. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease. [ABSTRACT FROM AUTHOR]

Leishmania major, the parasitic causative agent of leishmaniasis, produces a heme peroxidase (LmP), which catalyzes the peroxidation of mitochondrial cytochrome c (LmCytc) for protection from reactive oxygen species produced by the host. The association of LmP and LmCytc, which is known from kinetics measurements to be very fast (~108 M-1 s-1), does not involve major conformational changes and has been suggested to be dominated by electrostatic interactions. We used Brownian dynamics simulations to investigate the mechanism of formation of the LmP-LmCytc complex. Our simulations confirm the importance of electrostatic interactions involving the negatively charged D211 residue at the LmP active site, and reveal a previously unrecognized role in complex formation for negatively charged residues in helix A of LmP. The crystal structure of the D211N mutant of LmP reported herein is essentially identical to that of wild-type LmP, reinforcing the notion that it is the loss of charge at the active site, and not a change in structure, that reduces the association rate of the D211N variant of LmP. The Brownian dynamics simulations further show that complex formation occurs via a "bind and crawl" mechanism, in which LmCytc first docks to a location on helix A that is far from the active site, forming an initial encounter complex, and then moves along helix A to the active site. An atomistic molecular dynamics simulation confirms the helix A binding site, and steady state activity assays and stopped-flow kinetics measurements confirm the role of helix A charges in the association mechanism. [ABSTRACT FROM AUTHOR]

Thetau protein, whose aggregates are involved in Alzheimer’sdisease, is an intrinsically disordered protein (IDP) that regulatesmicrotubule activity in neurons. An IDP lacks a single, well-definedstructure and, rather, constantly exchanges among multiple conformations.In order to study IDP dynamics, the combination of experimental techniques,such as neutron scattering, and computational techniques, such asmolecular dynamics (MD) simulations, is a powerful approach. Amorphoushydrated powder samples have been very useful for studying proteininternal dynamics experimentally, e.g., using neutron scattering.Thus, there is demand for realistic in silico models of hydrated proteinpowders. Here we present an MD simulation analysis of a powder hydratedat 0.4 g water/g protein of the IDP tau in the temperature range 20–300K. By comparing with neutron scattering data, we identify the protein–waterinterface as the predominant feature determining IDP dynamics. Theso-called protein dynamical transition is shown to be attenuated,but not suppressed, in the parts of the protein that are not exposedto the solvent. In addition, we find similarities in the mean-squareddisplacements of the core of a globular protein and “dry”clusters formed by the IDP in hydrated powders. Thus, the ps to nsdynamics of proteins in hydrated powders originate mainly from thoseresidues in contact with solvent. We propose that by measuring thedynamics of protein assemblies, such as aggregates, one might assessqualitatively their state of hydration. [ABSTRACT FROM AUTHOR]

Specific ion interactions of KF, and the Na + salts of SO 4 2− , F − , Cl − , NO 3 − , I − , and ClO 4 − with benzene in aqueous solutions were investigated using molecular dynamics simulations and compared with experimental Raman multivariate curve resolution (Raman-MCR) and thermodynamic results. Good agreement is found with the hydration-shell partition coefficients of salts obtained from the thermodynamic analysis and of halogen anions obtained from the Raman-MCR spectra of benzene and pyridine. Larger discrepancies between the simulation and thermodynamic cation partitioning results point to the influence of counter-ion interaction on cation partitioning. [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]