Sickle Cell Hemoglobin "Drugged" with Cyclic Peptides Is Aggregation Incompetent.

Sickle cell disease (SCD) is a monogenic blood disorder associated with a mutation in the hemoglobin subunit β gene encoding for the β-globin of normal adult hemoglobin (HbA). This mutation transcribes into a Glu-β6 → Val-β6 substitution in the β-globins, inducing the polymerization of this hemoglobin form (HbS) when in the T-state. Despite advances in stem cell and gene therapy, and the recent approval of a new antisickling drug, therapeutic limitations persist.

Wild-Type α-Synuclein Structure and Aggregation: A Comprehensive Coarse-Grained and All-Atom Molecular Dynamics Study.

α-Synuclein (α-syn) is a 140 amino acid intrinsically disordered protein (IDP) and the primary component of cytotoxic oligomers implicated in the etiology of Parkinson's disease (PD). While IDPs lack a stable three-dimensional structure, they sample a heterogeneous ensemble of conformations that can, in principle, be assessed through molecular dynamics simulations. However, describing the structure and aggregation of large IDPs is challenging due to force field (FF) accuracy and sampling limitations.

Essential dynamics of ubiquitin in water and in a natural deep eutectic solvent.

Natural deep eutectic solvents (NADESs) comprised of osmolytes are of interest as potential biomolecular (cryo)protectants. However, the way these solvents influence the structure and dynamics of biomolecules as well as the role of water remains poorly understood. We carried out principal component analysis of various secondary structure elements of ubiquitin in water and a betaine : glycerol : water (1 : 2 : ; = 0, 1, 2, 5, 10, 20, 45) NADES, from molecular dynamics trajectories, to gain insight into the protein dynamics as it undergoes a transition from a highly viscous anhydrous to an aqueous environment.

Protein stability in a natural deep eutectic solvent: Preferential hydration or solvent slaving?

Deep eutectic solvents (DESs) emerged as potential alternative solvent media in multiple areas, including biomolecular (cryo)preservation. Herein, we studied the stability of a small protein (ubiquitin) in water and a betaine-glycerol-water (B:G:W) (1:2:ζ; ζ = 0, 1, 2, 5, 10) DES, through molecular dynamics. An AMBER-based model that accurately describes the density and shear viscosity of the DES is proposed.

Cyclic Peptides as Aggregation Inhibitors for Sickle Cell Disease.

Sickle cell disease is a missense genetic disorder characterized by the aggregation of deoxy-HbS into helical fibers that distort erythrocytes into a sickle-like shape. Herein, we investigate, through molecular dynamics, the effect of nine 5-mer cyclic peptides (CPs), tailor-designed to block key lateral contacts of the fibers. Our results show that the CPs bind orthogonally to the main HbS pocket involved in the latter contacts, with some revealing exceedingly long residence times.

Protein aggregation-inhibition: a therapeutic route from Parkinson's disease to sickle cell anemia.

Protein aggregation is implicated in multiple diseases, so-called proteinopathies, ranging from neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease (PD) to type 2 diabetes mellitus and sickle cell disease (SCD). The structure of the protein aggregates and the kinetics and mechanisms of aggregation have been the object of intense research over the years toward the development of therapeutic routes, including the design of aggregation inhibitors. Nonetheless, the rational design of drugs targeting aggregation inhibition remains a challenging endeavor because of multiple, disease-specific factors, including an incomplete understanding of protein function, the multitude of toxic and non-toxic protein aggregates, the lack of specific drug binding targets, discrepant action mechanisms of aggregation inhibitors, or a low selectivity, specificity, and/or drug potency, reflected in the high concentrations required for some inhibitors to be effective.

Mechanistic Insights into Polyphenols' Aggregation Inhibition of α-Synuclein and Related Peptides.

While several polyphenols were found to either inhibit or modulate the aggregation of proteins implicated in neurodegenerative diseases, such as Parkinson's disease (PD), discrepant action mechanisms have been reported. This, in addition to some polyphenols' pan-assay interference compounds' reputation, casts some doubts concerning their therapeutic relevance. Here, we studied, through molecular dynamics and enhanced sampling methods, the aggregation of 11-mer peptides from the non-amyloid-β component, an aggregation-prone domain of α-synuclein (α-syn) implicated in PD and other synucleinopathies, in neat water and aqueous solutions of resveratrol (RSV) and gallic acid (GA).

On the not so anomalous water-induced structural transformations of choline chloride-urea (reline) deep eutectic system.

The choline chloride-urea binary mixture in the molar ratio (1 : 2), commonly known as reline, is an archetypal solvent among deep eutectic solvents (DES). Neutron diffraction (ND) and empirical potential structure refinement (EPSR) results provided evidence that reline exhibits a peculiar structural transformation upon water addition that manifests in a sudden dewetting of the choline cations at ∼51 wt% water and, therefore, a non-monotonic variation of the choline-water and choline-choline coordination. Here, we study, through molecular dynamics (MD), the influence of water on the structure of a choline chloride : urea : water DES (1 : 2 : ; = 0 to 40), to gain additional insight into the molecular source of this peculiar structural transformation.

Aggregation of a Parkinson's Disease-Related Peptide: When Does Urea Weaken Hydrophobic Interactions?

While the exact cause of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease is not completely understood, compelling evidence implicates the aggregation of specific proteins and peptides. Co-solvents can provide molecular insight into protein aggregation mechanisms and the chemical nature of potential aggregation inhibitors. Here, we study, through molecular simulations, the hydration and binding free energies of an amphiphilic peptide from the nonamyloid-β component (NAC), a key aggregation-prone domain of α-synuclein, in water and an 8 M aqueous urea solution.

Structure and Dynamic Properties of a Glycerol-Betaine Deep Eutectic Solvent: When Does a DES Become an Aqueous Solution?

Deep eutectic solvents (DESs) are an emerging class of green solvents with a wide spectrum of potential applications whose properties may be further tailored through the addition of water. Here, we study, through molecular dynamics, the influence of water on the properties of a betaine-glycerol-water (B:G:W) DES (1:2:ζ; ζ = 0 to 100), aiming at getting insight into the structural and dynamic crossover between a DES and an aqueous solution. The density, shear viscosity, and diffusion coefficients are found to exhibit a non-linear dependence of ζ, similar to that observed for the solvation layers' composition.

Effect of urea on the hydration and aggregation of hydrophobic and amphiphilic solute models: Implications to protein aggregation.

Despite the emergence of a molecular picture of urea's protein unfolding mechanism in the past few decades, less is known about its action mechanism on protein aggregation. This is especially relevant for understanding the aggregation of amyloid proteins and peptides, implicated in several neurodegenerative diseases. While urea is believed to weaken the hydrophobic effect, a picture consistent with the decrease in the excess chemical potential of sufficiently large alkanes, interactions with protein polar side chains and backbone atoms are also important.

Exploring a near-Hartree-Fock-Kohn-Sham approach to study electronic properties of azobenzene in interaction with gold: From clusters to the Au(111) surface.

The electronic properties of azobenzene (AB) in interaction with gold clusters and adsorbed on the Au(111) surface are investigated by adopting a near-Hartree-Fock-Kohn-Sham (HFKS) scheme. This scheme relies on a hybrid Perdew-Burke-Ernzerhof functional, in which the exact non-local HF exchange contribution to the energy is taken as 3/4. Ionization energies and electron affinities for gas phase AB are in very good agreement with experimental data and outer valence Green's function) calculations.

Protein Denaturation, Zero Entropy Temperature, and the Structure of Water around Hydrophobic and Amphiphilic Solutes.

The hydrophobic effect plays a key role in many chemical and biological processes, including protein folding. Nonetheless, a comprehensive picture of the effect of temperature on hydrophobic hydration and protein denaturation remains elusive. Here, we study the effect of temperature on the hydration of model hydrophobic and amphiphilic solutes, through molecular dynamics, aiming at getting insight on the singular behavior of water, concerning the zero-entropy temperature, , and entropy convergence, , also observed for some proteins, upon denaturation.

On the Nonaggregation of Normal Adult Hemoglobin and the Aggregation of Sickle Cell Hemoglobin.

Sickle cell disease is a genetic disorder associated with a single mutation (Glu-β6 → Val-β6) in the β chains of hemoglobin, causing the polymerization of deoxygenated sickle cell hemoglobin (deoxy-HbS). The deoxy-HbS binding free energy was recently studied through molecular simulations, and a value of -14 ± 1 kcal mol was found. Here, we studied the binding free energy of normal adult hemoglobin (deoxy-HbA), which does not polymerize at normal physiological conditions, with the aim of elucidating the importance of the presence of Val-β6 and of the absence of Glu-β6 on the aggregation of deoxy-HbS.

Solubility of Polar and Nonpolar Aromatic Molecules in Subcritical Water: The Role of the Dielectric Constant.

Liquid water at temperatures above the boiling point and high pressures, also known as pressurized hot water, or subcritical water (SBCW), is an effective solvent for both polar and nonpolar organic solutes. This is often associated with the decrease of water's dielectric constant at high temperatures, apparently allowing water to behave like an organic solvent. The decrease of the solubility at high pressures, in turn, is explained by a mild increase of the dielectric constant of water.

Translational and rotational dynamics of high and low density TIP4P/2005 water.

We use molecular dynamics simulations using TIP4P/2005 to investigate the self- and distinct-van Hove functions for different local environments of water, classified using the local structure index as an order parameter. The orientational dynamics were studied through the calculation of the time-correlation functions of different-order Legendre polynomials in the OH-bond unit vector. We found that the translational and orientational dynamics are slower for molecules in a low-density local environment and correspondingly the mobility is enhanced upon increasing the local density, consistent with some previous works, but opposite to a recent study on the van Hove function.

Directing self-assembly in solution towards improved cooperativity in Fe(iii) complexes with amphiphilic tridentate ligands.

An amphiphilic iron(iii) complex with a tridentate Schiff-base ligand was prepared by condensation of a hexadecyloxy functionalised salycylaldehyde with a diamine followed by complexation with FeCl2 and anion methathesis with NaClO4. The complex shows spin crossover both in the solid state and solution. However in solution self-assembly and consequently aggregation of individual molecules form concentration dependent particles with sizes of 300 nm for higher concentrations, or 5 nm for lower concentrations.

On the Binding Free Energy and Molecular Origin of Sickle Cell Hemoglobin Aggregation.

Protein aggregation is associated with various diseases, including Alzheimer and Parkinson as well as sickle cell disease (SCD). From a molecular point of view, protein aggregation depends on a complex balance of electrostatic and hydrophobic interactions mediated by water. An impressive manifestation of the importance of this balance concerns the human hemoglobin (HbA) mutant, HbS (sickle cell Hb), where a single substitution at the 6th position of HbA β-chains, from glutamic acid to valine, causes the polymerization of deoxygenated HbS (deoxy-HbS), responsible for SCD.

Magnetic properties and core electron binding energies of liquid water.

The magnetic properties and the core and inner valence electron binding energies of liquid water are investigated. The adopted methodology relies on the combination of molecular dynamics and electronic structure calculations. Born-Oppenheimer molecular dynamics with the Becke and Lee-Yang-Parr functionals for exchange and correlation, respectively, and includes an empirical correction (BLYP-D3) functional and classical molecular dynamics with the TIP4P/2005-F model were carried out.

On the hydrogen-bond network and the non-Arrhenius transport properties of water.

We study the structural and dynamic transformations of SPC/E water with temperature, through molecular dynamics (MD), and discuss the non-Arrhenius behavior of the transport properties and orientational dynamics, and the magnitude of the breakdown of the Stokes-Einstein (SE) and the Stokes-Einstein-Debye (SED) relations, in the light of these transformations. Our results show that deviations from Arrhenius behavior of the self-diffusion at low temperatures cannot be exclusively explained by the reduction of water defects (interstitial waters) and the increase of the local tetrahedrality, thus, suggesting the importance of the slowdown of collective rearrangements. Interestingly we find that at high temperatures (T  ⩾  340 K) water defects lead to a slight increase of the tetrahedrality and a decrease of the self-diffusion, opposite to water at low temperatures.

Fast and slow dynamics and the local structure of liquid and supercooled water next to a hydrophobic amino acid.

We study, through molecular dynamics simulations, the structure and orientational dynamics of water next to a blocked hydrophobic amino acid, valine (Val), above and below the freezing point of water. The structure and the orientational dynamics of waters with four water neighbors (4WN) and less than four water neighbors (L4WN) in the Val's coordination sphere are deconvoluted. We find that in spite of the excluded volume effects waters with L4WN have faster librational dynamics than bulk water, reminiscent of water at the liquid-vapor interface, and faster orientational dynamics than waters with 4WN, at every temperature.

On the Structural and Dynamical Properties of DOPC Reverse Micelles.

The structure and dynamics of phospholipid reverse micelles are studied by molecular dynamics. We report all-atom unconstrained simulations of 1,2-dioleoyl-sn-phosphatidylcholine (DOPC) reverse micelles in benzene of increasing sizes, with water-to-surfactant number ratios ranging from W = 1 to 16. The aggregation number, i.

Ab initio calculation of the electronic absorption spectrum of liquid water.

The electronic absorption spectrum of liquid water was investigated by coupling a one-body energy decomposition scheme to configurations generated by classical and Born-Oppenheimer Molecular Dynamics (BOMD). A Frenkel exciton Hamiltonian formalism was adopted and the excitation energies in the liquid phase were calculated with the equation of motion coupled cluster with single and double excitations method. Molecular dynamics configurations were generated by different approaches.

Water tetrahedrons, hydrogen-bond dynamics, and the orientational mobility of water around hydrophobic solutes.

Despite being intensively studied, the magnitude of specific structural and dynamic perturbations of water next to hydrophobic surfaces remains a matter of debate. Here we show, from molecular dynamics, that the structure of a subset of water molecules in the first hydration layer, those preserving four nearest water neighbors, resembles that of water at ∼10 °C, and that the origin of the orientational slowdown is mainly a decrease of the hydrogen-bond (HB) acceptor switch frequency, while water structuring plays a minor role, slightly accelerating HB acceptor switches. By portraying the mean HB dynamics of water as a doubly periodic event, we demonstrate that the orientational retardation factor is effectively defined by the ratio of the HB acceptor switch period in the hydration layer and bulk.