In this study, we investigated the stability of the fully activated conformation of the orexin receptor 2 (OX2R) embedded in a pure POPC bilayer using MD simulations. Various thermodynamic ensembles (i.e., NPT, NVT, NVE, NPAT, μVT, and NPγT) were employed to explore the dynamical heterogeneity of the system in a comprehensive way. In addition, informational similarity metrics (e.g., Jensen-Shannon divergence) as well as Markov state modeling approaches were utilized to elucidate the receptor kinetics. Special attention was paid to assessing surface tension within the simulation box, particularly under NPγT conditions, where 21 nominal surface tension constants were evaluated. Our findings suggest that traditional thermodynamic ensembles such as NPT may not adequately control physical properties of the POPC membrane, impacting the plausibility of the OX2R model. In general, the performed study underscores the importance of employing the NPγT ensemble for computational investigations of membrane-embedded receptors, as it effectively maintains zero surface tension in the simulated system. These results offer valuable insights for future research aimed at understanding receptor dynamics and designing targeted therapeutics.
- MeSH
- fosfatidylcholiny * chemie MeSH
- lipidové dvojvrstvy chemie metabolismus MeSH
- Markovovy řetězce * MeSH
- orexinové receptory * chemie metabolismus MeSH
- povrchové napětí * MeSH
- simulace molekulární dynamiky * MeSH
- termodynamika * MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 1-palmitoyl-2-oleoylphosphatidylcholine MeSH Prohlížeč
- fosfatidylcholiny * MeSH
- lipidové dvojvrstvy MeSH
- orexinové receptory * MeSH
The structural response of 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC)/water bilayers to addition and subsequent solvation of a small amphiphilic molecule - an anesthetic benzyl alcohol - was studied by means of solid-state NMR (2H NMR, 31P NMR) spectroscopy and low-angle X-ray diffraction. The sites of binding of this solute molecule within the bilayer were determined - the solute was shown to partition between several sites in the bilayer and the equilibrium was shown to be dynamic and dependent on the level of hydration and temperature. At the same time, it was shown that solubilization of benzyl alcohol reached a solubility limit and was terminated when the ordering profile of DMPC hydrocarbon chains adopted finite limiting values throughout the whole chain. Such findings were made probably for the first time for any lipid bilayer system and possibly have more general implications for dissolution of other small-molecule amphiphilic solutes in lipid bilayer systems other than DMPC. The limit to the hydrocarbon chain profile is probably a more general property and corresponds to the balance of intrabilayer and interbilayer forces established in combination with the elastic properties of the bilayer system that still consists of one single phase just before the solute forms an excess phase. It is not necessary to quantify the contribution of each individual intrabilayer and interbilayer force acting within such a bilayer system. A model of the dependence of surface density of lipid chains on the chain segment order parameter was also developed - an empirical mathematical model based on experimental data was derived and it was proposed to represent a relationship between intrinsic bilayer forces and bilayer deformation characteristics and might be proven to be of more general significance in the future.
- MeSH
- anestetika chemie MeSH
- benzylalkohol chemie MeSH
- difrakce rentgenového záření MeSH
- dimyristoylfosfatidylcholin * chemie MeSH
- lipidové dvojvrstvy * chemie MeSH
- magnetická rezonanční spektroskopie MeSH
- molekulární struktura MeSH
- povrchově aktivní látky chemie MeSH
- rozpustnost * MeSH
- voda chemie MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- anestetika MeSH
- benzylalkohol MeSH
- dimyristoylfosfatidylcholin * MeSH
- lipidové dvojvrstvy * MeSH
- povrchově aktivní látky MeSH
- voda MeSH
Dry skin is a common condition that is experienced by many. Besides being particularly present during the cold season, various diseases exist all year round, leading to localized xerosis. To prevent it, the skin is provided with natural moisturizing factors (NMFs). They are small amino acids or derivatives found in the outermost layer of the skin, the stratum corneum (SC). They are often claimed to be highly efficient humectants, increasing the water content to maintain the fluidity of the skin. However, alternative mechanisms have been proposed, suggesting that NMFs themselves may act as lipid mobility amplifiers. This work aims at investigating the role of three NMFs, namely, urea (URE), glycerol (GLY), and urocanic acid/urocanate (UCA/UCO) in SC in silico models, considering two different levels of humidity. Molecular dynamic simulations showed an increase in the diffusion of different lipid components, mainly free fatty acids (FFAs) and ceramide acyl chain moieties, in the presence of either high water content or NMFs. The membrane properties were modified, as seen by an increased thickness and greater lateral stiffness. All NMFs exhibited a similar impact, whereas UCA revealed slight differences according to its charged state. By studying NMF-water intermolecular interactions, we highlighted the role of NMF as a regulator of membrane perturbations while ensuring membrane fluidity. This role allows NMFs to prevent destabilization of the skin membrane in the presence of high water content. This study, performed at an atomistic resolution, highlighted a strong H-bond network between lipids involving mainly ceramides but also all other components. This network can be modified in the presence of a high water concentration or NMFs, resulting in modifications of membrane properties, rationalizing hydration effects.
- MeSH
- glycerol * chemie MeSH
- kůže * chemie metabolismus MeSH
- kyselina urokanová chemie metabolismus MeSH
- lidé MeSH
- močovina * chemie MeSH
- simulace molekulární dynamiky * MeSH
- voda * chemie MeSH
- vodíková vazba * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- glycerol * MeSH
- kyselina urokanová MeSH
- močovina * MeSH
- voda * MeSH
In nature and many technological applications, aqueous solutions are in contact with patterned surfaces, which are dynamic over time scales spanning from ps to μs. For instance, in biology, exposed polar and apolar residues of biomolecules form a pattern, which fluctuates in time due to side chain and conformational motions. At metal/and oxide/water interfaces, the pattern is formed by surface topmost atoms, and fluctuations are due to, e.g., local surface polarization and rearrangements in the adsorbed water layer. All these dynamics have the potential to influence key processes such as wetting, energy relaxation, and biological function. Yet, their impact on the water H-bond network remains often elusive. Here, we leverage molecular dynamics to address this fundamental question at a self-assembled monolayer (SAM)/water interface, where ns dynamics is induced by frustrating SAM-water interactions via methylation of the terminal -OH groups of poly(ethylene glycol) (PEG) chains. We find that surface dynamics couples to the water H-bond network, inducing a response on the same ns time scale. This leads to time fluctuations of local wetting, oscillating from hydrophobic to hydrophilic environments. Our results suggest that rather than average properties, it is the local─ both in time and space─ solvation that determines the chemical-physical properties of dynamically patterned surfaces in water.
- Publikační typ
- časopisecké články MeSH
This manuscript presents a comprehensive study on the quantification of modifier molecules adsorbed on gold nanoparticles (AuNPs) using two complementary techniques Ellman's method (UV-vis spectroscopy) and isothermal titration calorimetry (ITC). In this paper, we compare the feasibility of using the ITC technique and Ellman's method to study the interactions of mercaptosulfonate compounds (sodium mercaptoethanesulfonate, MES, and sodium mercaptoundecanesulfonate, MUS) with the surface of AuNPs of various sizes. The thermodynamic functions of the attachment of mercaptosulfonates to AuNPs were determined, revealing a linear relationship between the number of adsorbed molecules and the surface area of the nanoparticles. The amount of MES and MUS determined by Ellman's method (7 and 11 molecules per square nm, respectively) is more than twice that measured by the ITC technique (3 and 4 molecules per square nm, respectively). The slight differences in the adsorption of MES and MUS on the gold surface are due to differences in the carbon chain length of the ligand molecules. In the case of MES, the formation of the Au-S bond is the dominant stage of the adsorption process, whereas for MUS, the ordering process and self-assembly of molecules on the gold surface are dominant.
- Publikační typ
- časopisecké články MeSH
The knowledge of viscosity behavior, crystal growth phenomenon, and diffusion is important in producing, processing, and practical applications of amorphous solids prepared in different forms (bulk glasses and thin films). This work uses microscopy to study volume crystal growth in Ge25Se75 bulk glasses and thermally evaporated thin films. The collected growth data measured over a wide temperature range show a significant increase in crystal growth rates in thin films. The crystal growth is analyzed using near-surface viscosities obtained in bulks and thin films using nanoindentation and melt viscosities measured by a pressure-assisted melt filling technique. The crystal growth analysis provides information on the size of the structural units incorporated into the growing crystals, essential for estimating the diffusion coefficients and explaining the difference in crystal growth rates in bulk and thin films. The crystal growth analysis also reveals the decoupling between diffusion and viscous flow described by the Stokes-Einstein-Eyring relation. Moreover, to the authors' best knowledge, the manuscript provides the first evaluation estimation of the effective self-diffusion coefficient directly from growth data in chalcogenide glass-formers. The present data show a similar relation between diffusion coefficients (D) and crystal growth rates (u): u ≈ D0.87, which is found in several molecular glasses.
- Publikační typ
- časopisecké články MeSH
Protein-protein interactions, controlling protein aggregation in the solution phase, are crucial for the formulation of protein therapeutics and the use of proteins in diagnostic applications. Additives in the solution phase are factors that may enhance the protein's conformational stability or induce crystallization. Protein-PEG interactions do not always stabilize the native protein structure. Structural information is needed to validate excipients for protein stabilization in the development of protein therapeutics or use proteins in diagnostic assays. The present study investigates the impact of polyethylene glycol (PEG) molecular weight and concentration on the spatial structure of human hemoglobin (Hb) at neutral pH. Small-angle X-ray scattering (SAXS) in combination with size-exclusion chromatography is employed to characterize the Hb structure in solution without and with the addition of PEG. Our results evidence that human hemoglobin maintains a tetrameric conformation at neutral pH. The dummy atom model, reconstructed from the SAXS data, aligns closely with the known crystallographic structure of methemoglobin (metHb) from the Protein Data Bank. We established that the addition of short-chain PEG600, at concentrations of up to 10% (w/v), acts as a stabilizer for hemoglobin, preserving its spatial structure without significant alterations. By contrast, 5% (w/v) PEG with higher molecular weights of 2000 and 4000 leads to a slight reduction in the maximum particle dimension (Dmax), while the radius of gyration (Rg) remains essentially unchanged. This implies a reduced hydration shell around the protein due to the dehydrating effect of longer PEG chains. At a concentration of 10% (w/v), PEG2000 interacts with Hb to form a complex that does not distort the protein's spatial configuration. The obtained results provide a deeper understanding of PEG's influence on the Hb structure in solution and broader knowledge regarding protein-PEG interactions.
- MeSH
- difrakce rentgenového záření * MeSH
- hemoglobiny * chemie MeSH
- koncentrace vodíkových iontů MeSH
- krystalizace * MeSH
- lidé MeSH
- maloúhlový rozptyl * MeSH
- molekulární modely MeSH
- molekulová hmotnost MeSH
- polyethylenglykoly * chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- hemoglobiny * MeSH
- polyethylenglykoly * MeSH
N6-Methyladenosine (m6A) is a prevalent RNA post-transcriptional modification that plays crucial roles in RNA stability, structural dynamics, and interactions with proteins. The YT521-B (YTH) family of proteins, which are notable m6A readers, functions through its highly conserved YTH domain. Recent structural investigations and molecular dynamics (MD) simulations have shed light on the mechanism of recognition of m6A by the YTHDC1 protein. Despite advancements, using MD to predict the stabilization induced by m6A on the free energy of binding between RNA and YTH proteins remains challenging due to inaccuracy of the employed force field and limited sampling. For instance, simulations often fail to sufficiently capture the hydration dynamics of the binding pocket. This study addresses these challenges through an innovative methodology that integrates metadynamics, alchemical simulations, and force-field refinement. Importantly, our research identifies hydration of the binding pocket as giving only a minor contribution to the binding free energy and emphasizes the critical importance of precisely tuning force-field parameters to experimental data. By employing a fitting strategy built on alchemical calculations, we refine the m6A partial charge parameters, thereby enabling the simultaneous reproduction of N6 methylation on both the protein binding free energy and the thermodynamic stability of nine RNA duplexes. Our findings underscore the sensitivity of binding free energies to partial charges, highlighting the necessity for thorough parametrization and validation against experimental observations across a range of structural contexts.
- MeSH
- adenosin * analogy a deriváty chemie metabolismus MeSH
- metylace MeSH
- proteiny vázající RNA chemie metabolismus MeSH
- RNA * chemie metabolismus MeSH
- simulace molekulární dynamiky * MeSH
- termodynamika * MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- adenosin * MeSH
- N-methyladenosine MeSH Prohlížeč
- proteiny vázající RNA MeSH
- RNA * MeSH
Although polymers are widely used in laser-irradiation research, their microscopic response to high-intensity ultrafast XUV and X-ray irradiation is still largely unknown. Here, we comparatively study a homologous series of alkenes. The XTANT-3 hybrid simulation toolkit is used to determine their damage kinetics and irradiation threshold doses. The code simultaneously models the nonequilibrium electron kinetics, the energy transfer between electrons and atoms via nonadiabatic electron-ion (electron-phonon) coupling, nonthermal modification of the interatomic potential due to electronic excitation, and the ensuing atomic response and damage formation. It is shown that the lowest damage threshold is associated with local defect creation, such as dehydrogenation, various group detachments from the backbone, or polymer strand cross-linking. At higher doses, the disintegration of the molecules leads to a transient metallic liquid state: a nonequilibrium superionic state outside of the material phase diagram. We identify nonthermal effects as the leading mechanism of damage, whereas the thermal (nonadiabatic electron-ion coupling) channel influences the kinetics only slightly in the case of femtosecond-pulse irradiation. Despite the notably different properties of the studied alkene polymers, the ultrafast-X-ray damage threshold doses are found to be very close to ∼0.05 eV/atom in all three materials: polyethylene, polypropylene, and polybutylene.
- Publikační typ
- časopisecké články MeSH
Despite ongoing research on antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs), their precise translocation mechanism remains elusive. This includes Buforin 2 (BF2), a well-known AMP, for which spontaneous translocation across the membrane has been proposed but a high barrier has been calculated. Here, we used computer simulations to investigate the effect of a nonequilibrium situation where the peptides are adsorbed on one side of the lipid bilayer, mimicking experimental conditions. We demonstrated that the asymmetric membrane adsorption of BF2 enhances its translocation across the lipid bilayer by lowering the energy barrier by tens of kJ mol-1. We showed that asymmetric membrane adsorption also reduced the free energy barrier of lipid flip-flop but remained unlikely even at BF2 surface saturation. These results provide insight into the driving forces behind membrane translocation of cell-penetrating peptides in nonequilibrium conditions, mimicking experiments.
- MeSH
- adsorpce MeSH
- antimikrobiální peptidy chemie farmakologie MeSH
- buněčná membrána metabolismus chemie MeSH
- kationické antimikrobiální peptidy chemie farmakologie metabolismus MeSH
- lipidové dvojvrstvy * chemie metabolismus MeSH
- penetrační peptidy chemie metabolismus MeSH
- proteiny MeSH
- simulace molekulární dynamiky MeSH
- termodynamika MeSH
- terpeny chemie farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antimikrobiální peptidy MeSH
- buforin II MeSH Prohlížeč
- kationické antimikrobiální peptidy MeSH
- lipidové dvojvrstvy * MeSH
- penetrační peptidy MeSH
- proteiny MeSH
- terpeny MeSH
