Molecular Dynamics Simulations Of Water Research Articles

Exploring the Functional Landscape of the p53 Regulatory Domain: The Stabilizing Role of Post-Translational Modifications.

This study focuses on the intrinsically disordered regulatory domain of p53 and the impact of post-translational modifications. Through fully atomistic explicit water molecular dynamics simulations, we show the wealth of information and detailed understanding that can be obtained by varying the number of phosphorylated amino acids and implementing a restriction in the conformational entropy of the N-termini of that intrinsically disordered region. The take-home message for the reader is to achieve a detailed understanding of the impact of phosphorylation with respect to (1) the conformational dynamics and flexibility, (2) structural effects, (3) protein interactivity, and (4) energy landscapes and conformational ensembles. Although our model system is the regulatory domain p53 of the tumor suppressor protein p53, this study contributes to understanding the general effects of intrinsically disordered phosphorylated proteins and the impact of phosphorylated groups, more specifically, how minor changes in the primary sequence can affect the properties mentioned above.

Influence of the Dielectric Constant on the Ionic Current Rectification of Bipolar Nanopores.

In this paper, we investigate how the dielectric constant, ϵ, of an electrolyte solvent influences the current rectification characteristics of bipolar nanopores. It is well recognized that bipolar nanopores with two oppositely charged regions rectify current when exposed to an alternating electric potential difference. Here, we consider dilute electrolytes with NaCl only and with a mixture of NaCl and charged nanoparticles. These systems are studied using two levels of description, all-atom explicit water molecular dynamics (MD) simulations and coarse-grained implicit solvent MD simulations. The charge density and electric potential profiles and current-voltage relationship predicted by the implicit solvent simulations with ϵ = 11.3 show good agreement with the predictions from the explicit water simulations. Under nonequilibrium conditions, the predictions of the implicit solvent simulations with a dielectric constant closer to the one of bulk water are significantly different from the predictions obtained with the explicit water model. These findings are closely aligned with experimental data on the dielectric constant of water when confined to nanometric spaces, which suggests that ϵ decreases significantly compared to its value in the bulk. Moreover, the largest electric current rectification is observed in systems containing nanoparticles when ϵ = 78.8. Using enhanced sampling, we have shown that this larger rectification arises from the presence of a significantly deeper minimum in the free energy of the system with a larger ϵ, and when a negative voltage bias is applied. Since implicit solvent models and mean-field continuum theories are often used to design Janus membranes based on bipolar nanopores, this work highlights the importance of properly accounting for the effects of confinement on the dielectric constant of the electrolyte solvent. The results presented here indicate that the dielectric constant in implicit solvent simulations may be used as an adjustable parameter to approximately account for the effects of nanometric confinement on aqueous electrolyte solvents.

Effect of caffeine on the aggregation of amyloid-β-A 3D RISM study.

Alzheimer's disease is a detrimental neurological disorder caused by the formation of amyloid fibrils due to the aggregation of amyloid-β peptide. The primary therapeutic approaches for treating Alzheimer's disease are targeted to prevent this amyloid fibril formation using potential inhibitor molecules. The discovery of such inhibitor molecules poses a formidable challenge to the design of anti-amyloid drugs. This study investigates the effect of caffeine on dimer formation of the full-length amyloid-β using a combined approach of all-atom, explicit water molecular dynamics simulations and the three-dimensional reference interaction site model theory. The change in the hydration free energy of amyloid-β dimer, with and without the inhibitor molecules, is calculated with respect to the monomeric amyloid-β, where the hydration free energy is decomposed into energetic and entropic components, respectively. Dimerization is accompanied by a positive change in the partial molar volume. Dimer formation is spontaneous, which implies a decrease in the hydration free energy. However, a reverse trend is observed for the dimer with inhibitor molecules. It is observed that the negatively charged residues primarily contribute for the formation of the amyloid-β dimer. A residue-wise decomposition reveals that hydration/dehydration of the side-chain atoms of the charged amino acid residues primarily contribute to dimerization.

Study of absorption and emission spectra of substituted terthiophene compounds by methods of theoretical chemistry.

Terthiophene derivatives attract interest due to their prospective applications in optoelectronic or sensor devices. Due to their nontoxicity they can be considered as suitable candidates in biological applications. Supramolecular organization of the matter is one of the most interesting topics in contemporary materials science. Amphiphilic chromophores based on substituted terthiophenes are capable of self-assembly into supramolecular architectures. In this work, we aim at simulation of the spectral properties of terthiophene with oligo(ethylene oxide) substituents by the methods of quantum chemistry and molecular dynamics (MD). The potential energy surface (PES) of this molecule was determined by the methods of density functional theory (DFT) for the ground state and time-dependent density-functional theory (TD-DFT) for the excited state. MD simulations in water than revealed the most frequented molecular conformations in both these states. Absorption and fluorescence spectra were determined for all these conformations, including the surrounding water molecules, using TD-DFT and averaged over the conformation space to obtain the final absorption and fluorescence spectrum. The calculated spectra were compared with their experimental counterparts and the differences were discussed in context of the supramolecular structure revealed by confocal microscopy. In spite of its simplicity, this approach provides a satisfactory approximation of absorption and fluorescent spectra of these molecules obtained by computational methods.

Electrofreezing of liquid water at ambient conditions

Water is routinely exposed to external electric fields. Whether, for example, at physiological conditions, in contact with biological systems, or at the interface of polar surfaces in countless technological settings, water responds to fields on the order of a few V Å−1 in a manner that is under intense investigation. Dating back to the 19th century, the possibility of solidifying water upon applying electric fields – a process known as electrofreezing – is an alluring promise that has canalized major efforts since, with uncertain outcomes. Here, we perform long (up to 500 ps per field strength) ab initio molecular dynamics simulations of water at ambient conditions under external electric fields. We show that fields of 0.10 − 0.15 V Å−1 induce electrofreezing to a ferroelectric amorphous phase which we term f-GW (ferroelectric glassy water). The transition occurs after ~ 150 ps for a field of 0.15 V Å−1 and after ~ 200 ps for a field of 0.10 V Å−1 and is signaled by a structural and dynamic arrest and the suppression of the fluctuations of the hydrogen bond network. Our work reports evidence of electrofreezing of bulk liquid water at ambient conditions and therefore impacts several fields, from fundamental chemical physics to biology and catalysis.

Permeability of C-S-H

Hydrodynamics in calcium silicate hydrates nanopores are crucial to concrete’s durability and confinement performance. Here, Non-Equilibrium Molecular Dynamics simulations of water confined in-between C-S-H layers are reported considering slit pore sizes spanning interlayer and gel pores. These simulations enable the computation of the permeability of C-S-H and the quantification of the boundary conditions associated with the flow. A tensorial formalism is applied to describe this forced flow accounting for the pore wall texture and resulting stick/slip boundary conditions. As for other properties, shear viscosity also shows a significant pore-size dependence at the nanoscale. The adoption of slip boundary conditions and confinement-dependent viscosity is crucial to capturing the water permeability of the C-S-H gel. The fundamental link between self-diffusion and viscosity (following the Einstein–Stokes equation) describes the temperature dependence of hydrodynamics.

What do far-infrared spectra of solitary water in "water-in-solvent" systems reveal about water's solvation and dynamics?

Classical molecular dynamics simulations of water in ionic and dipolar solvents were used to interpret the far-infrared (FIR) rotation/libration spectra of "solitary water" in terms of water's rotational dynamics and interactions with solvents. Seven solvents represented by nonpolarizable all-atom force fields and a series of idealized variable-charge solvents were used to span the range of solvent polarities (hydrogen bonding) studied experimentally. Simulated spectra capture the solvent dependence observed, as well as the relationship between the frequencies of water libration (νL) and OH stretching bands (νOH). In more strongly interacting solvents, simulated νL are ∼20% higher than those of experiment. In all solvents, the simulated spectra are composites of rotational motions about the two axes perpendicular to water's dipole moment, and the different frequencies of these two motions are responsible for the breadth of the libration band and the bimodal shape observed in halide ionic liquids. Simulations overestimate the separation of these two components in most solvents. The character of water rotational motions changes markedly with solvent polarity, from quasi-free rotation in nonpolar and weakly polar solvents to highly constrained libration in strongly hydrogen bonding environments. The changeover to librational motions dominating the spectrum occurs between solvents such as benzene (νL ∼ 250cm-1) and acetonitrile (νL ∼ 400cm-1). For solvents in the latter category, the mean frequency of the experimental FIR band provides a direct measure of mean-squared torques and, therefore, force constants associated with interactions constraining water's librational motion.

Interaction of Water and Oxygen Molecules with Phosphorene: An Ab Initio Study.

Phosphorene, the 2D form of black phosphorus, has recently attracted interest for optoelectronic and tribological applications. However, its promising properties are affected by the strong tendency of the layers to oxidize in ambient conditions. A significant effort has been made to identify the role of oxygen and water in the oxidation process. In this work, we introduce a first-principles study of the phosphorene phase diagram and provide a quantitative estimate of the interaction of pristine and fully oxidized phosphorene layers with oxygen and water molecules. Specifically, we study oxidized layers with oxygen coverages of 25% and 50% that keep the typical anisotropic structure of the layers. We found that hydroxilated and hydrogenated phosphorene layers are both energetically unfavorable, leading to structural distortions. We also studied the water physisorption on both pristine and oxidized layers, finding that the adsorption energy gain doubled on the oxidized layers, whereas dissociative chemisorption was always energetically unfavorable. At the same time, further oxidation (i.e., the dissociative chemisorption of O2) was always favorable, even on oxidized layers. Ab initio molecular dynamics simulations of water intercalated between sliding phosphorene layers showed that even under harsh tribological conditions water dissociation was not activated, thus further strengthening the results obtained from our static calculations. Overall, our results provide a quantitative description of the interaction of phosphorene with chemical species that are commonly found in ambient conditions at different concentrations. The phase diagram that we introduced confirms the tendency of phosphorene layers to fully oxidize due to the presence of O2, resulting in a material with improved hydrophilicity, a piece of information that is relevant for the application of phosphorene, e.g., as a solid lubricant. At the same time, the structural deformations found for the H- and OH- terminated layers undermine their electrical, mechanical, and tribological anisotropic properties and, therefore, the usage of phosphorene.

In silico characterization of the psilocybin biosynthesis pathway

Nearly all mushrooms of the Psilocybe genus contain the natural product psilocybin, which is a psychoactive alkaloid derived from l-tryptophan. Considering their use in ancient times, as well as their psychedelic properties, these mushrooms have re-emerged with psychotherapeutic potential for treating depression, which has triggered increased pharmaceutical interest. However, the psilocybin biosynthesis pathway was only recently defined and, as such, little exists in the way of structural data. Accordingly, the aim of this study was to structurally characterize this pathway by generating homology models for the four Psilocybe cubensis enzymes involved in psilocybin biosynthesis (PsiD, a decarboxylase; PsiH, a monooxygenase; PsiK, a phosphotransferase; PsiM, a methyltransferase). Following initial model generation and alignment with the identified structural templates, repeated refinement of the models was carried out using secondary structure prediction, geometry evaluation, energy minimization, and molecular dynamics simulations in water. The final models were then evaluated using molecular docking interactions with their substrates, i.e., psilocybin precursors (l-tryptophan, tryptamine, 4-hydroxytryptamine, and norbaeocystin/baeocystin), all of which generated feasible binding modes for the expected biotransformation. Further plausibility of the psilocybin → aeruginascin, 4-hydroxytryptamine → norpsilocin, and tryptamine → N,N-dimethyltryptamine conversions, all mediated by the generated model for PsiM, suggests valid routes of formation for these key secondary metabolites. The structural characterization of these enzymes and their binding modes which emerged from this study can lead to a better understanding of psilocybin synthesis, thereby paving the way for the development of novel substrates and selective inhibitors, as well as improved biotechnological manipulation and production of psilocybin in vitro.

Strange layer structure of dipolar spins formed on the spin-ice lattice

Monte Carlo simulations of dipolar spins on a spin-ice lattice were carried to explore the effect of the long-range interaction. The simulation with finite-range cutoff found formation of a layer-like structure, whereas that with Ewald found no layer. This feature characterized with the dipolar orientation and the distance-dependent Kirkwood factor GK(R) is consistent with that known for water molecular dynamics simulation. This correspondence found between the different systems of water and lattice spin will be important knowledge for understanding the relationship between the long-range interaction and the structure formation.

Analyzing the binding affinity of potential homodimers produced by the C55 portion of the amyloid precursor protein, a molecular dynamics study.

Alzheimer's disease is a neurodegenerative disease that affects millions of people in the United States alone. Agglomeration of amyloid beta (Aβ) peptides is a potential cause of the disease and the loss of mental acuity it induces. Aβ is created via the cleavage of the amyloid precursor protein (APP). When APP is cleaved, part of it—approximately the C99 fragment—remains in the lipid membrane, with its N-terminus being the Aβ peptide. The dimerization of C99 is theorized to limit its further cleavage and thereby limit the production of Aβ. However, this has yet to be proven experimentally. The first 55 residues of the C99 fragment (called C55) contains both the transmembrane domain and Aβ. In this work, we explored multiple potential conformations of C55 dimers (starting from the PDB ID 2LP1) and calculated their binding affinity to better understand the viability of homodimerization. The homodimer conformations were explored using both implicit and explicit water Molecular Dynamics simulations. We used an Extended Adaptive Biasing Force method to calculate the binding affinity of these dimers in a POPC lipid membrane. This methodology is characterized by the use of a continuously updated biasing force that cancels all force along a specified reaction coordinate and, in this way, enables uniform sampling on a flat free-energy surface. Applying this methodology using collective variables for root-mean-square deviation, spin, tilt, and Euclidean distance for both the bulk (monomer) and bound (dimer) states, we compute a binding affinity of roughly −4 kcal/mol for one of our dimer conformations. This lends in silica credence to the hypothesis that the dimerization of C55 limits the formation of Aβ, as the dimer appears energetically viable.

Aggregation propensities of proteins with varying degrees of disorder.

The hydration thermodynamics of a globular protein (AcP), three intrinsically disordered protein regions (1CD3, 1MVF, 1F0R) and a fully disordered protein (α-synuclein) is studied by an approach that combines an all-atom explicit water molecular dynamics simulations and three-dimensional reference interaction site model (3D-RISM) theory. The variation in hydration free energy with percentage disorder of the selected proteins is investigated through its nonelectrostatic and electrostatic components. A decrease in hydration free energy is observed with an increase in percentage disorder, indicating favorable interactions of the disordered proteins with the solvent. This confirms the role of percentage disorder in determining the aggregation propensity of proteins which is measured in terms of the hydration free energy in addition to their respective mean net charge and mean hydrophobicity. The hydration free energy is decoupled into energetic and entropic terms. A residue-wise decomposition analysis of the hydration free energy for the selected proteins is evaluated. The decomposition shows that the disordered regions contribute more than the ordered ones for the intrinsically disordered protein regions. The dominant role of electrostatic interactions is confirmed from the residue-wise decomposition of the hydration free energy. The results depict that the negatively charged residues contribute more to the total hydration free energy for the proteins with negative mean net charge, while the positively charged residues contribute more for proteins with positive mean net charge.

Capturing the Recognition Dynamics of para-Sulfonato-calix[4]arenes by Cytochrome c: Toward a Quantitative Free Energy Assessment.

Calix[n]arenes' selective recognition of protein surfaces covers a broad range of timely applications, from controlling protein assembly and crystallization to trapping partially disordered proteins. Here, the interaction of para-sulfonated calix-[4]-arenes with cytochrome c is investigated through all-atom, explicit water molecular dynamics simulations which allow characterization of two binding sites in quantitative agreement with experimental evidence. Free energy calculations based on the MM-PBSA and the attach-pull-release (APR) methods highlight key residues implicated in the recognition process and provide binding free energy results in quantitative agreement with isothermal titration calorimetry. Our study emphasizes the role of MD simulations to capture and describe the "walk" of sulfonated calix-[4]-arenes on the cytochrome c surface, with the arginine R13 as a pivotal interacting residue. Our MD investigation allows, through the quasi-harmonic multibasin (QHMB) method, probing an allosteric reinforcement of several per-residue interactions upon calixarene binding, which suggests a more complex mode of action of these supramolecular auxiliaries.

Porous aromatic framework coated stir bar sorptive extraction coupled with gas chromatography for the analysis of 16 polycyclic aromatic hydrocarbons in atmospheric particles and environmental water samples

In this work, porous aromatic frameworks (PAFs) with different pore size were evaluated for simultaneous adsorption of 16 polycyclic aromatic hydrocarbons (PAHs) with large difference in polarity and molecular size. Two other porous organic polymers containing electron pushing/withdrawing group were investigated along for a comparison, and PAF-120 with the pore size of appr. 2.1 nm exhibited the highest extraction efficiency. Based on water contact angle and molecular dynamics simulation, the adsorption of 16 PAHs on PAF-120 was attributed to hydrophobic interaction, π-π interaction and molecular sieving effect. PAF-120/PDMS coated stir bar was then prepared by physical adhesion, and a method of stir bar sorptive extraction-gas chromatography-flame ionization detector was established for trace PAHs analysis in environmental samples. Under the optimal experimental conditions, the limits of detection (S/N = 3) for 16 PAHs were found to be in the range of 42-375 ng/L, with the relative standard deviations of 4.1-14.6% (n = 7). The enrichment factors varied from 31 (Indeno[1,2,3-cd]pyrene) to 80-fold (anthracene), with the maximal enrichment factor of 100-fold. The proposed method was applied to the analysis of PAHs in local environmental water and atmospheric particle samples. None of the 16 PAHs were detected in the collected water samples. While for the collected atmospheric particles, 12 PAHs were detected in fine particulate matter (PM2.5) within the range of 0.6-2.8 ng/m3. For inhalable particulate matter (PM10) and total suspended particulate matter (TSP), 16 PAHs were all detected in the range of 0.6-3.8 ng/m3 and 0.6-5.9 ng/m3, respectively. Quantitative recoveries were obtained in recovery test, demonstrating the accuracy and application potential of the proposed method.

Diffusion and Entropy of Supercooled Water in Nanoslit

Understanding the supercooled water behaviors in different circumstances is essential and provides the foundation to apply. The behaviors of supercooled water in nanoslit haven’t been studied yet, though these of supercooled bulk water were studied about wo decades ago. Here molecular dynamics simulations of water were conducted to investigate the diffusion and structures in nanoslit systematically. The diffusion coefficient of water close to the graphene sheets decreased with increasing pressure which was different from bulk water. The diffusion was strongly related to excess entropy. The existence of graphene sheets caused the layered water. Further, the water layer close to graphene sheets preferred ordered triangular and square to pentagonal and hexagonal structures.

Molecular dynamics simulations of structural and dynamical aspects of DNA hydration water

Water is a remarkable liquid, both because of it is intriguing but also because of its importance. Water plays a key role on the structure and function of biological molecules, but on the other hand also the structure and dynamics of water are deeply influenced by its interactions with biological molecules, specially at low temperatures, where water’s anomalies are enhanced. Here we present extensive molecular dynamics simulations of water hydrating a oligonucleotide down to very low temperatures (supercooled water), comparing four water models and analyzing the water structure and dynamics in different domains: water in the minor groove, water in the major groove and bulk water. We found that the water in the grooves is slowed down by the interactions with the nucleic acid and a hints of a dynamic transition regarding translational and orientational dynamics were found, specially for the water models TIP4P/2005 and TIP4P-Ew, which also showed the closest agreement with available experimental data. The behavior of water in such extreme conditions is relevant for the study of cryopreservation of biological tissues.

Comparison of molecular dynamics simulations of water with neutron and X-ray scattering experiments

The atomistic structure and dynamics obtained from molecular dynamics (MD) simulations with the example of TIP3P (rigid and flexible) and TIP4P/2005 (rigid) water is compared to neutron and X-ray scattering data at ambient conditions. Neutron and X-ray diffractograms are calculated from the simulations for four isotopic substitutions as well as the incoherent intermediate scattering function for neutrons. The resulting curves are compared to each other and to published experimental data. Differences between simulated and measured intermediate scattering functions are quantified by fitting an analytic model to the computed values. The sensitivity of the scattering curves to the parameters of the MD simulations is demonstrated on the example of two parameters, bond length and angle.

Water as a Lévy Rotor.

A probability density function describing the angular evolution of a fixed-length atom-atom vector as a Lévy rotor is derived containing just two dynamical parameters: the Lévy parameter α and a rotational time constant τ. A Lévy parameter α<2 signals anomalous (non-Brownian) motion. Molecular dynamics simulation of water at 298K validates the probability density function for the intramolecular ^{1}H─^{1}H dynamics. The rotational dynamics of water is found to be approximately Brownian at subpicosecond time intervals, becomes increasingly anomalous at longer time intervals due to hydrogen-bond breaking and reforming, before becoming indistinguishable from Brownian dynamics beyond about 25ps. The Lévy rotor model is used to estimate the intramolecular contribution to the longitudinal nuclear-magnetic-resonance (NMR) relaxation rate R_{1,intra}. It is found that R_{1,intra} contributes 65%±7% to the overall relaxation rate of water at room temperature.

Polarizable Water Potential Derived from a Model Electron Density.

A new empirical potential for efficient, large scale molecular dynamics simulation of water is presented. The HIPPO (Hydrogen-like Intermolecular Polarizable POtential) force field is based upon the model electron density of a hydrogen-like atom. This framework is used to derive and parametrize individual terms describing charge penetration damped permanent electrostatics, damped polarization, charge transfer, anisotropic Pauli repulsion, and damped dispersion interactions. Initial parameter values were fit to Symmetry Adapted Perturbation Theory (SAPT) energy components for ten water dimer configurations, as well as the radial and angular dependence of the canonical dimer. The SAPT-based parameters were then systematically refined to extend the treatment to water bulk phases. The final HIPPO water model provides a balanced representation of a wide variety of properties of gas phase clusters, liquid water, and ice polymorphs, across a range of temperatures and pressures. This water potential yields a rationalization of water structure, dynamics, and thermodynamics explicitly correlated with an ab initio energy decomposition, while providing a level of accuracy comparable or superior to previous polarizable atomic multipole force fields. The HIPPO water model serves as a cornerstone around which similarly detailed physics-based models can be developed for additional molecular species.

Hydrosulfide (HS−) Recognition and Sensing in Water by Halogen Bonding Hosts

AbstractHydrogen sulfide (H2S) plays a crucial signalling role in a variety of physiological systems, existing as the hydrosulfide anion (HS−) at physiological pH. Combining the potency of halogen bonding (XB) for anion recognition in water with coumarin fluorophore incorporation in acyclic host structural design, the first XB receptors to bind and, more importantly, sense the hydrosulfide anion in pure water in a reversible chemosensing fashion are demonstrated. The XB receptors exhibit characteristic selective quenching of fluorescence upon binding to HS−. Computational DFT and molecular dynamics simulations in water corroborate the experimental anion binding observations, revealing the mode and nature of HS− recognition by the XB receptors.