Ángel Piñeiro

Refractive indices, molar volumes and molar refractions of binary liquid mixtures: concepts and correlations

Prompted by the observation that recent literature displays marked disagreement as to the proper treatment of data on the refractive indices of binary liquid mixtures, this paper clarifies the relationships among refractive index, molar volume and molar refraction and the corresponding mixing properties. It is shown that the molar refraction deviation function must be calculated on a mole fraction basis and the refractive index deviation function on a volume fraction basis, which makes it directly interpretable as a sign-reversed measure of the deviation of reduced free volume from ideality.

Molecular Dynamics Simulations of Phosphatidylcholine Membranes: A Comparative Force Field Study

Molecular dynamics simulations provide a route to studying the dynamics of lipid bilayers at atomistic or near atomistic resolution. Over the past 10 years or so, molecular dynamics simulations have become an established part of the biophysicists tool kit for the study of model biological membranes. As simulation time scales move from tens to hundreds of nanoseconds and beyond, it is timely to re-evaluate the accuracy of simulation models. We describe a comparative analysis of five freely available force fields that are commonly used to model lipid bilayers. We focus our analysis on 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayers. We show that some bilayer properties have a pronounced force field dependence, while others are less sensitive. In general, we find strengths and weaknesses, with respect to experimental data, in all of the force fields we have studied. We do, however, find some combinations of simulation and force field parameters that should be avoided when simulating DPPC and POPC membranes. We anticipate that the results presented for some of the membrane properties will guide future improvements for several force fields studied in this work.

Refractive indexes of binary mixtures of tetrahydrofuran with 1-alkanols at 25°C and temperature dependence of n and ρ for the pure liquids

Refractive indexes at 25°C were measured for binary mixtures of tetrahydrofuran with 1-hexanol, 1-heptanol, 1-octanol, 1-nonanol, and 1-decanol. Densities, from which excess molar volumes were derived, were measured at the same temperature for the system tetrahydrofuran + 1-decanol. Refractive indexes and densities for the pure compounds were determined at 11 temperatures between 20 and 30°C. The thermal expansion coefficients and the temperature derivatives of the refractive index for these liquids were calculated at 25°C. The temperature dependence of the molar refraction was also examined. The contribution to the molar refraction of a CH2 group was calculated as was the difference between contributions from CH3 and CH2OH groups. The change of molar refraction on mixing is d iscussed in terms of molecular interactions and alkyl chain length.

Prediction of excess volumes and excess surface tensions from experimental refractive indices

Abstract Refractive indices for the binary liquid mixtures: {hexane or heptane + ethanol}, {o-xylene + benzene} and {cyclohexane + benzene, toluene or hexane} were measured at 298.15 K. Excess refractive indices were calculated and fitted to a Redlich-Kister function. Using some mixture rules (Lorentz-Lorenz, Dale -Gladstone, Eykman, Oster, Arago-Biot and Newton), predictions for vE have been made and compared with experimental data taken from the literature. Furthermore the Sugden equation has been used in two different ways for predicting excess surface tensions: the first one starting from densities and the other one from refractive indices. Results are plotted together with the literature data.

Similarities and differences between cyclodextrin-sodium dodecyl sulfate host-guest complexes of different stoichiometries: molecular dynamics simulations at several temperatures.

An extensive dynamic and structural characterization of the supramolecular complexes that can be formed by mixing α-, β-, and γ-cyclodextrin (CD) with sodium dodecyl sulfate (SDS) in water at 283, 298, and 323 K was performed by means of computational molecular dynamics simulations. For each CD at the three temperatures, seven different initial conformations were used, generating a total of 63 trajectories. The observed stoichiometries, intermolecular distances, and relative orientation of the individual molecules in the complexes, as well as the most important interactions which contribute to their stability and the role of the solvent water molecules were studied in detail, revealing clear differences and similarities between the three CDs. Earlier reported findings in the inclusion complexes field are also discussed in the context of the present results. For any of the three native cyclodextrins, the CD(2)SDS(1) species in the head-to-head conformation appears to be a promising building block for nanotubular aggregates both in the bulk and at the solution/air interface, as earlier suggested for the case of α-CD. Moreover, the observed noninclusion arrangements involving β-CD are proposed as the seed for the premicellar (β-CD)-induced aggregation of SDS described in the literature.

Modeling and Molecular Dynamics Simulation of the Human Gonadotropin-Releasing Hormone Receptor in a Lipid Bilayer

In the present study, a model for the human gonadotropin-releasing hormone receptor embedded in an explicit lipid bilayer was developed. The final conformation was obtained by extensive molecular dynamics simulations of a homology model based on the bovine rhodopsin crystal structure. The analysis of the receptor structure allowed us to detect a number of specific contacts between different amino acid residues, as well as water- and lipid-mediated interactions. These interactions were stable in six additional independent 35 ns long simulations at 310 and 323 K, which used the refined model as the starting structure. All loops, particularly the extracellular loop 2 and the intracellular loop 3, exhibited high fluctuations, whereas the transmembrane helices were more static. Although other models of this receptor have been previously developed, none of them have been subjected to extensive molecular dynamics simulations, and no other three-dimensional structure is publicly available. Our results suggest that the presence of ions as well as explicit solvent and lipid molecules are critical for the structure of membrane protein models, and that molecular dynamics simulations are certainly useful for their refinement.

Functional and Structural Roles of Conserved Cysteine Residues in the Carboxyl-Terminal Domain of the Follicle-Stimulating Hormone Receptor in Human Embryonic Kidney 293 Cells

The carboxyl-terminal segment of G protein-coupled receptors has one or more conserved cysteine residues that are potential sites for palmitoylation. This posttranslational modification contributes to membrane association, internalization, and membrane targeting of proteins. In contrast to other members of the glycoprotein hormone receptor family (the LH and thyroid-stimulating hormone receptors), it is not known whether the follicle-stimulating hormone receptor (FSHR) is palmitoylated and what are the effects of abolishing its potential palmitoylation sites. In the present study, a functional analysis of the FSHR carboxyl-terminal segment cysteine residues was carried out. We constructed a series of mutant FSHRs by substituting cysteine residues with alanine, serine, or threonine individually and together at positions 629 and 655 (conserved cysteines) and 627 (nonconserved). The results showed that all three cysteine residues are palmitoylated but that only modification at Cys629 is functionally relevant. The lack of palmitoylation does not appear to greatly impair coupling to G(s) but, when absent at position 629, does significantly impair cell surface membrane expression of the partially palmitoylated receptor. All FSHR Cys mutants were capable of binding agonist with the same affinity as the wild-type receptor and internalizing on agonist stimulation. Molecular dynamics simulations at a time scale of approximately 100 nsec revealed that replacement of Cys629 resulted in structures that differed significantly from that of the wild-type receptor. Thus, deviations from wild-type conformation may potentially contribute to the severe impairment in plasma membrane expression and the modest effects on signaling exhibited by the receptors modified in this particular position.

Multiscale molecular dynamics simulations of micelles: coarse-grain for self-assembly and atomic resolution for finer details†

A positional interpolation/extrapolation method for the mapping of coarse-grained (CG) to atomistic (AT) resolution is presented and tested for single-component micelles formed by lysophospholipids of different chain length. The target CG nanoaggregates were self-assembled from random mixtures of surfactants in explicit MARTINI water and equilibrated by molecular dynamics simulations, at the microsecond time scale. The ambiguity inherent in the definition of the CG particles was explored by mapping the same CG structures to AT resolution surfactants of different size. After the conversion, the obtained AT micelles were simulated for 250 ns and the resulting trajectories were analyzed in detail. The mean lifetime of the surfactant–solvent interactions as well as the lateral diffusion coefficients of the surfactant molecules within the micellar aggregates were obtained for the first time. The results suggest that the individual molecules within the micelle behave like lipids in a fluid membrane. The employed mapping back method is efficient and versatile, as it can be applied to diverse combinations of force fields and systems with a minimum of code development. In a general context, this work illustrates the power of multiscale molecular dynamics simulations for the generation and subsequent examination of self-assembled structures, including the fine characterization of structural and dynamic properties of the resulting aggregate.

A Critical Approach to the Thermodynamic Characterization of Inclusion Complexes: Multiple-Temperature Isothermal Titration Calorimetric Studies of Native Cyclodextrins with Sodium Dodecyl Sulfate

Inclusion complexes based on native cyclodextrins are basic building blocks for the design of a new generation of promising materials. The design process can be optimized by maximizing the population of the desired chemical species. This is greatly facilitated by an accurate characterization of the thermodynamic parameters for their formation. A critically assessed literature review of equilibrium constants for cyclodextrin:sodium dodecyl sulfate (CD:SDS) complexes is reported. We performed multiple-temperature isothermal titration calorimetric (283-323 K) measurements for these systems, leading to the first reported heat capacity changes of binding. Data were analyzed using two thermodynamic models by homemade programs that also provide the distribution of chemical species as a function of the experimental variables. Assisted by earlier molecular dynamic simulations, a microscopic-level discussion of the contributions to the thermodynamic parameters is given. On the basis of our results, a number of recommendations to obtain reliable association parameters for CD-based inclusion complexes are listed.

Surface Adsorption and Bulk Aggregation of Cyclodextrins by Computational Molecular Dynamics Simulations as a Function of Temperature: α-CD vs β-CD

The structural simplicity of native cyclodextrins (CDs) contrasts with their complex behavior in the bulk of aqueous solutions, mainly when they are combined with other cosolutes. Many scientific and industrial applications based on these molecules are supported only by empirical information. The lack of fundamental knowledge, which would allow one to rationally optimize many of these applications, is notable mainly at the solution/air interface. Basic information on phenomena such as the spontaneous adsorption of native CDs or on the structure of CD aggregates in the bulk solution is really scarce. In order to fill these gaps, a detailed computational study on the adsorption and aggregation of α- and β-CDs as a function of temperature is presented here. Our simulations reproduce, at atomic resolution, the experimentally observed much higher ability of β-CD to aggregate compared to that of α-CD at 298 K, as well as their dependence on temperature. The adsorption of both individual CDs and small CD aggregates (up to 20 molecules) to the solution/air interface is found to be negligible. 0.8 μs long trajectories of single CD molecules in aqueous solution reveal that the main differences in the behavior of both CDs are their flexibility, higher for β-CD, and the occupancy of individual intramolecular hydrogen bonds that is significantly longer for the same cyclodextrin. The aggregation pattern of α- and β-CDs is followed at the hundreds of ns time scale, allowing both the spontaneous self-assembly of cyclodextrins and their redistribution along the aggregates to be observed. This is the first attempt to study the adsorption and aggregation of native cyclodextrins by atomistic molecular dynamics simulations.