Explicit Description Of Solvent Research Articles

Ion Partition in Polyelectrolyte Gels and Nanogels.

Polyelectrolyte gels provide a load-bearing structural framework for many macroscopic biological tissues, along with the organelles within the cells composing tissues and the extracellular matrices linking the cells at a larger length scale than the cells. In addition, they also provide a medium for the selective transportation and sequestration of ions and molecules necessary for life. Motivated by these diverse problems, we focus on modeling ion partitioning in polyelectrolyte gels immersed in a solution with a single type of ionic valence, i.e., monovalent or divalent salts. Specifically, we investigate the distribution of ions inside the gel structure and compare it with the bulk, i.e., away from the gel structure. In this first exploratory study, we neglect solvation effects in our gel by modeling the gels without an explicit solvent description, with the understanding that such an approach may be inadequate for describing ion partitioning in real polyelectrolyte gels. We see that this type of model is nonetheless a natural reference point for considering gels with solvation. Based on our idealized polymer network model without explicit solvent, we find that the ion partition coefficients scale with the salt concentration, and the ion partition coefficient for divalent ions is higher than for monovalent ions over a wide range of Bjerrum length (lB) values. For gels having both monovalent and divalent salts, we find that divalent ions exhibit higher ion partition coefficients than monovalent salt for low divalent salt concentrations and low lB. However, we also find evidence that the neglect of an explicit solvent, and thus solvation, provides an inadequate description when compared to experimental observations. Thus, in future work, we must consider both ion and polymer solvation to obtain a more realistic description of ion partitioning in polyelectrolyte gels.

Explicit solvent repulsive scaling replica exchange molecular dynamics (RS-REMD) in molecular modeling of protein-glycosaminoglycan complexes.

Glycosaminoglcyans (GAGs), linear anionic periodic polysaccharides, are crucial for many biologically relevant functions in the extracellular matrix. By interacting with proteins GAGs mediate processes such as cancer development, cell proliferation and the onset of neurodegenerative diseases. Despite this eminent importance of GAGs, they still represent a limited focus for the computational community in comparison to other classes of biomolecules. Therefore, there is a lack of modeling tools designed specifically for docking GAGs. One has to rely on existing docking software developed mostly for small drug molecules substantially differing from GAGs in their basic physico-chemical properties. In this study, we present an updated protocol for docking GAGs based on the Repulsive Scaling Replica Exchange Molecular Dynamics (RS-REMD) that includes explicit solvent description. The use of this water model improved docking performance both in terms of its accuracy and speed. This method represents a significant computational progress in GAG-related research.

Prediction of the interaction strength of an urea‐based probe toward ions in water by means of Density Functional Theory/Polarizable Continuum Model calculations

AbstractWe study numerically, by means of density functional theory (DFT) calculations complemented with an implicit solvation model, a novel chemical probe bearing urea and aromatic phenyl groups. We probe the interaction in water of the latter with a wide variety of ions relevant to water quality. We perform geometry minimizations using PBE0 functional and aug‐cc‐pVDZ basis set, and a polarizable continuum model (PCM) to take into account the aqueous solvent. We underline for the first time several methodological details concerning the definition of thebindingorinteractionenergy, and the basis set superposition error definition in the context of implicit solvation models. We observe two competing interaction modes for this probe: a urea‐enhanced, cation‐πinteraction (with cations only), and hydrogen bonding occurring between the urea group and anions, the former being more favorable than the latter. A Generalized Kohn–Sham Energy Decomposition Analysis (GKS‐EDA) in implicit solvent is performed to analyze the nature of the ions–probe interactions. Magnesium and sodium ions, and respectively glyphosate and hypochlorite ions, are found as the cations (resp. anions) having the largest binding free energies with the probe. This is the first time such an exhaustive study, investigating the selectivity of an organic probe toward a wide variety of ions in water, is carried out in the context of DFT/PCM models. Computer‐aided sensor design needs reliable and efficient methods. Our methodology can be used as a general way to gain a valuable insight into the sensitivity of organic ligands toward a variety of ions or pesticides in water, without the need of an explicit solvent description, but still going beyond the state‐of‐the‐art DFT in vacuo approach. By predicting possible competitive interactions, and understanding their nature, this methodology can thus help to better design functional groups selective to specific targets.

Exploring Free Energy Profiles of Enantioselective Organocatalytic Aldol Reactions under Full Solvent Influence.

We present a computational study on the enantioselectivity of organocatalytic proline-catalyzed aldol reactions between aldehydes in dimethylformamide (DMF). To explore the free energy surface of the reaction, we apply two-dimensional metadynamics on top of ab initio molecular dynamics (AIMD) simulations with explicit solvent description on the DFT level of theory. We avoid unwanted side reactions by utilizing our newly developed hybrid AIMD (HyAIMD) simulation scheme, which adds a simple force field to the AIMD simulation to prevent unwanted bond breaking and formation. Our condensed phase simulation results are able to nicely reproduce the experimental findings, including the main stereoisomer that is formed, and give a correct qualitative prediction of the change in syn:anti product ratio with different substituents. Furthermore, we give a microscopic explanation for the selectivity. We show that both the explicit description of the solvent and the inclusion of entropic effects are vital to a good outcome—metadynamics simulations in vacuum and static nudged elastic band (NEB) calculations yield significantly worse predictions when compared to the experiment. The approach described here can be applied to a plethora of other enantioselective or organocatalytic reactions, enabling us to tune the catalyst or determine the solvent with the highest stereoselectivity.

Structure and dynamics of atactic Na+-poly(acrylic) acid (PAA) polyelectrolyte in aqueous solution in dilute, semi-dilute and concentrated regimes

ABSTRACTStructural and dynamic properties of aqueous solution of atactic poly(acrylic) acid (PAA) in dilute, semi-dilute and concentrated regimes were studied by fully atomistic molecular dynamics simulations with explicit solvent description, as a function of polymer concentration c (i.e. volume fraction φp) and charge density f. PAA size (Rg, R) decreases with φp in semi-dilute and concentrated regimes, due to increase in counter-ion condensation. For all values of f, in dilute regime (c < c*) chains are expanded and in semi-dilute regime (c*< c < c**) chains are in contact with each other, while for c ≅ c** aggregates comprising of few PAA chains occur (at f = 0.2, 0.4 and 0.7). Number of PAA intrachain h-bonds is greater than PAA–PAA interchain h-bonds at all values of f and φp. The number of h-bonds between carboxylic acid groups and carboxylate groups remain unaffected by φp. The Na+ ion self-diffusion coefficient shows linear decrease with concentration for f < 1 and exponential decrease for f = 1. The PAA self-diffusion coefficient shows power law decrease with concentration for f < 1 and exponential decrease for f = 1. Aggregation of chains is favoured due to PAA–PAA interactions with increase in concentration. Our simulation results are in agreement with experiments and coarse-grained simulations in the literature.

Pushing the Limits of Structure-Based Models: Prediction of Nonglobular Protein Folding and Fibrils Formation with Go-Model Simulations.

The development of computational efficient models is essential to obtain a detailed characterization of the mechanisms underlying the folding of proteins and the formation of amyloid fibrils. Structure-based computational models (Go-model) with Cα or all-atom resolutions have been able to successfully delineate the mechanisms of folding of several globular proteins and offer an interesting alternative to computationally intensive simulations with explicit solvent description. Here, we explore the limits of Go-model predictions by analyzing the folding of the nonglobular repeat domain proteins Notch Ankyrin and p16INK4 and the formation of human islet amyloid polypeptide (hIAPP) fibrils. Folding trajectories of the repeat domain proteins revealed that an all-atom resolution is required to capture the folding pathways and cooperativity reported in experimental studies. The all-atom Go-model was also successful in predicting the free-energy landscape of hIAPP fibrillation, suggesting a "dock and lock" mechanism of fibril elongation. We finally explored how mutations can affect the co-assembly of hIAPP fibrils by simulating a heterogeneous system composed of wild-type and mutated hIAPP peptides. Overall, this study shows that all-atom Go-model-based simulations have the potential of discerning the effects of mutations and post-translational modifications in protein folding and association and may help in resolving the dichotomy between experimental and theoretical studies on protein folding and amyloid fibrillation.

A computational study of samarium diiodide-induced cyclizations of N-oxoalkyl-substituted methyl indole-3-carboxylates-A rationale of the diastereoselectivity.

A detailed model for the reaction mechanism of the samarium diiodide (SmI2 ) mediated reductive coupling of N-oxoalkyl-substituted methyl indole-3-carboxylates is developed in this study by determining the Gibbs energies for the intermediates of possible reaction pathways. The Gibbs energies at ambient temperature are calculated with dispersion corrected density functional theory in combination with implicit (D-COSMO-RS) and explicit solvent description. Temperature dependent ro-vibrational contributions are considered with the help of statistical thermodynamics. In contrast to previous proposals for the reaction mechanism, the high diastereoselectivity in the cyclization is found to be due to the formation of an energetically highly favorable chelate complex in which the final relative configuration is already preformed. After cyclization and a second electron transfer, alkylation of the resulting anion takes place under kinetic control from the more "open" face whereas protonation is under thermodynamic control. The calculations are in good agreement with these experimental findings. © 2017 Wiley Periodicals, Inc.

Effect of water on the local electric potential of simulated ionic micelles.

Ionic micelles in an aqueous solution containing single-charged counter-ions have been simulated by molecular dynamics. For both cationic and anionic micelles, it has been demonstrated that explicit description of solvent has strong effect on the micelle's electric field. The sign of the local charge alters in the immediate vicinity of the micellar crown and the electric potential varies nonmonotonically. Two micelle models have been examined: the hybrid model with a rigid hydrocarbon core and the atomistic model. For three molecular models of water (Simple Point Charge model (SPC), Transferable Intermolecular Potential 5- Points (TIP5P) and two-centered S2), the results have been compared with those for the continuum solvent model. The orientational ordering of solvent molecules has strong effect on the local electric field surprisingly far from the micelle surface.

Wetting of a solid substrate by a “civilized” model of ionic solutions

We use classical density functional theory (DFT) and an explicit solvent description to investigate the wetting and drying behavior of ionic solutions in contact with a charged solid substrate. The solvent is modeled by dipolar hard spheres, while the monovalent ions are oppositely charged hard spheres; cohesion is ensured by a Yukawa attraction between all three species. The free energy functional describing the inhomogeneous solution includes the best available fundamental measure description of excluded volume correlations in a ternary mixture of hard spheres, whereas all electrostatic and cohesive interactions are treated within the mean-field approximation. We find both first and second order wetting transitions which are rather little affected by ions at low and moderate concentrations, compared to the wetting behavior of the pure solvent. A novel drying scenario is predicted, where complete drying is prevented by the electrostatic attraction between a positively charged substrate and the anions, while near a negatively charged substrate, a first order transition with a predrying line is observed. The various scenarios are surprisingly similar to our previous predictions based on a "semiprimitive" model where the solvent particles carry no dipole, but the ion-ion interactions are reduced by a local dielectric permittivity.

A Collective Variable for the Efficient Exploration of Protein Beta-Sheet Structures: Application to SH3 and GB1.

We introduce a new class of collective variables which allow forming efficiently beta-sheet structures in all-atom explicit-solvent simulations of proteins. By this approach we are able to systematically fold a 16-residue beta hairpin using metadynamics on a single replica. Application to the 56-residue SH3 and GB1 proteins show that, starting from extended states, in ∼100 ns tens of structures containing more than 30% beta-sheet are obtained, including parts of the native fold. Using these variables may allow folding moderate size proteins with an accurate explicit solvent description. Moreover, it may allow investigating the presence of misfolded states that are relevant for diseases (e.g., prion and Alzheimer) and studying beta-aggregation (amyloid diseases).

Understanding DNA Based Nanostructures

We use molecular dynamics (MD) simulations to understand the structure, and stability of various Paranemic crossover (PX) DNA molecules and their topoisomer JX molecules, synthesized recently by Seeman and coworkers at New York University (NYU). Our studies include all atoms (4432 to 6215) of the PX structures with an explicit description of solvent and ions (for a total of up to 42,000 atoms) with periodic boundary conditions. We report the effect of divalent counterions Mg(+2) on the structural and thermodynamic properties of these molecules and compare them to our previously reported results in presence of monovalent Na+ ions. The dynamic structures averaged over the 3-nanosecond simulations preserves the Watson-Crick hydrogen bonding as well as the helical structure. We find that PX65 is the most stable structure both in Na+ and Mg(+2) in accordance with the experimental results. PX65 has helical twist and other helical structural parameters close to the values for normal B-DNA of similar length and sequence. Our strain energy calculations demonstrate that stability of the crossover structure increases with the increase in crossover points.

Atomic-Level Simulations of Seeman DNA Nanostructures: The Paranemic Crossover in Salt Solution

We use molecular dynamics (MD) simulations to understand the structure and stability of various paranemic crossover (PX) DNA molecules, synthesized recently by Seeman and co-workers at New York University. These studies include all atoms of the PX structures with an explicit description of solvent and ions. The average dynamics structures over the last 1 ns of the 3-ns simulation preserve the Watson-Crick hydrogen bonding as well as the helical structure. The root mean-square deviation in coordinates with respect to the MD averaged structure converges to 2–3 Å for PX55, PX65, and PX85, but for PX75 and PX95 the root mean-square deviation in coordinates exhibits large fluctuations, indicating an intrinsic instability. The PX structures are structurally more rigid compared to the canonical B-DNA without crossover. We have developed a strain energy analysis method based on the nearest-neighbor interaction and computed the strain energy for the PX molecules compared to the B-DNA molecules of the same length and sequence. PX65 has the lowest calculated strain energy (∼−0.77 kcal/mol/bp), and the strain increases dramatically for PX75, PX85, and PX95. PX55 has the highest strain energy (∼1.85 kcal/mol/bp) making it unstable, which is in accordance with the experimental results. We find that PX65 has helical twist and other helical structural parameters close to the values for normal B-DNA of similar length and sequence. Vibrational mode analysis shows that compared to other PX motifs, PX65 has the smallest population of the low-frequency modes that are dominant contributors for the conformational entropy of the PX DNA structures. All these results indicate that PX65 is structurally more stable compared to other PX motifs, in agreement with experiments. These results should aid in designing optimized DNA structures for use in nanoscale components and devices.

Understanding the Optical Band Shape: Coumarin-153 Steady-State Spectroscopy

We have developed a band-shape analysis of optical transitions in polarizable chromophores characterized by large magnitudes of the transition dipole (intense transitions). The model is tested on steady-state spectra of the coumarin-153 optical dye, employing an explicit solvent description accounting for dipole moment, quadrupole moment, and polarizability of the solvent molecules. The calculations are performed for solvents ranging from nondipolar to strongly dipolar. The solvent dependence of both the experimental Stokes shift and the spectral width is satisfactorily reproduced over the whole polarity range. The optical width is shown to demonstrate a qualitatively different solvent dependence for absorption and emission. The solvent-induced absorption width increases with solvent polarity, whereas the solvent-induced emission width passes through a maximum. This is a result of non-Gaussian statistics of the energy gap fluctuations in polarizable/electronically delocalized chromophores. The total (i.e., solvent and vibrational) emission width tends to pass through a broad maximum at low solvent polarities, decreasing with solvent polarity for highly polar solvents. This results from the combined influence of a solvent-induced mixing of the vacuum adiabatic states and a decrease of the vibrational reorganization energy with increasing solvent polarity. The latter effect arises as a result of a coupling of the vibrational and solvent nuclear modes due to the electronic state occupation number difference, making the vibrational reorganization energy solvent-dependent. The study revels a breakdown of the linear relation between the solvent-induced width and Stokes shift. The model suggests that the Franck−Condon factor of intense optical lines should significantly depend on the magnitude of the transition dipole.

Structure, Dynamics and Energetics of Initiation Sites in Protein Folding: I. Analysis of a 1 ns Molecular Dynamics Trajectory of an Early Folding Unit in Water: The Helix I/Loop I-Fragment of Barnase

The dynamic and energetic behavior of an initiation site of protein folding (helix I/loop I fragment of barnase) isolated from the tertiary environment of the rest protein is investigated in a 1 ns molecular dynamics simulation. All atom representation, explicit solvent description, and periodic boundary conditions are applied. In the course of the simulation several steps of structural disintegration are observed, followed by events partially rebuilding the initial structure. The phase of disintegration results in a fragment conformation completely lacking hydrogen bonds, with one residue in the center of the helix changed from α to β conformation. The transition state of helix disintegration is characterized by a complete i⇒ i+4/ i+5hydrogen bonding network which undergoes gradual hydrolysis starting at the solvent exposed flank and proceeding towards the interior of the fragment perpendicular to the axis of the helix. Energetic analysis of the helix transitions shows that the i⇒ i+4/ i⇒ i+5 network of hydrogen bonds accommodates one helical residue in β conformation with only slightly worse hydrogen bonding energy and Van der Waals packing compared to the regular α-helix. The stability of the fragment is primarily due to hydrophobic interactions of residues shown to be essential in mutagenesis experiments. f2 f2 Permanent address: F. Avbelj, Institute of Chemistry, Hajdrihova 19, 61001 Ljubljana, Slovenia. Abbreviations used: ASA, (solvent) accessible surface area; EFU, early folding unit; MD, molecular dynamics; NMR, nuclear magnetic resonance (spectroscopy); RMS(D), root mean square (deviation).