The Journal of Physical Chemistry B最新文献

The research presented in this paper focuses on the EWS-FLI1 oncoprotein, a critical factor in Ewing sarcoma, a rare and lethal cancer primarily affecting children and young adults. Through molecular dynamics and quantum mechanics analyses, the study explores the reactivity properties of six snapshots of the EWS-FLI1 oncoprotein, aiming to contribute to the development of targeted therapies. The investigation emphasizes the significance of understanding the molecular behavior of EWS-FLI1 for effective treatment development, utilizing computational methods such as density functional theory. The findings suggest that EWS-FLI1 is a compact, electrophilic protein with localized reactive sites, providing valuable insights for potential drug development and enhancing our knowledge of Ewing sarcoma for targeted treatments.

Cyclometalated iridium(III) complexes are increasingly being developed for application in G-quadruplex (GQ) nucleic acid biosensors. We monitored the interactions of a GQ structure with an iridium(III) complex by nuclear magnetic resonance (NMR) titrations and subsequently compared the binding site inferred from NMR with binding positions modeled by molecular docking and molecular dynamics simulations. When titrated into a solution of G-quadruplex Pu22T, compound 1(PF₆), [Ir(ppy)₂(pizp)](PF₆), where ppy is 2-phenylpyridine and pizp is 2-phenylimidazole[4,5f][1,10]phenanthroline, had the greatest impact on the hydrogen chemical shifts of G5, G8, G9, G13, and G17 residues of Pu22T, indicating end-stacking at the 5' tetrad. In blind cross-docking studies with Autodock 4, end-stacking at the 5' tetrad was found as the lowest energy binding position. AMBER molecular dynamics simulations resulted in a refined binding position at the 5' tetrad with improved pi stacking. For this model system, Pu22T-1, molecular docking and molecular dynamics simulations are tools that are able to predict the experimentally determined binding position.

The viscosity and diffusion properties of crowded protein systems were investigated with molecular dynamics simulations of SH3 mixtures with different crowders, and results were compared with experimental data. The simulations accurately reproduced experimental trends across a wide range of protein concentrations, including highly crowded environments up to 300 g/L. Notably, viscosity increased with crowding but varied little between different crowder types, while diffusion rates were significantly reduced depending on protein-protein interaction strength. Analysis using the Stokes-Einstein relation indicated that the reduction in diffusion exceeded what was expected from viscosity changes alone, with the additional slow-down attributable to transient cluster formation driven by weakly attractive interactions. Contact kinetics analysis further revealed that longer-lived interactions contributed more significantly to reduced diffusion rates than short-lived interactions. This study also highlights the accuracy of current computational methodologies for capturing the dynamics of proteins in highly concentrated solutions and provides insights into the molecular mechanisms affecting protein mobility in crowded environments.

A profound understanding of protein structure and mechanism requires dedicated experimental and theoretical tools to elucidate electrostatic and hydrogen bonding interactions in proteins. In this work, we employed an approach to disentangle noncovalent and hydrogen-bonding electric field changes during the reaction cascade of a multidomain protein, i.e., the phytochrome Agp2. The approach exploits the spectroscopic properties of nitrile probes commonly used as reporter groups of the vibrational Stark effect. These probes were introduced into the protein through site-specific incorporation of noncanonical amino acids resulting in four variants with different positions and orientations of the nitrile groups. All substitutions left structures and the reaction mechanism unchanged. Structural models of the dark states (Pfr) were used to evaluate the total electric field at the nitrile label and its transition dipole moment. These quantities served as an internal standard to calculate the respective properties of the photoinduced products (Lumi-F, Meta-F, and Pr) based on the relative intensities of the nitrile stretching bands. In most cases, the spectral analysis revealed two substates with a nitrile in a hydrogen-bonded or hydrophobic environment. Using frequencies and intensities, we managed to extract the noncovalent contribution of the electric field from the individual substates. This analysis resulted in profiles of the noncovalent and hydrogen-bond-related electric fields during the photoinduced reaction cascade of Agp2. These profiles, which vary significantly among the four variants due to the different positions and orientations of the nitrile probes, were discussed in the context of the molecular events along the Pfr → Pr reaction cascade.

Oxidized lipids arising from oxidative stress are associated with many serious health conditions, including cardiovascular diseases. For example, KDdiA-PC and KOdiA-PC are two oxidized phosphatidylcholines (oxPC) directly linked to atherosclerosis, which precipitate heart failure, stroke, aneurysms, and chronic kidney disease. These oxPCs are well-characterized in small particles such as low-density lipoprotein, but how their presence affects the biophysical properties of larger bilayer membranes is unclear. It is also unclear how membrane mediators, such as cholesterol, affect lipid bilayers containing these oxPCs. Here, we characterize supported lipid bilayers (SLBs) containing POPC, KDdiA-PC, or KOdiA-PC, and cholesterol. We used a quartz crystal microbalance with dissipation monitoring (QCM-D), fluorescence microscopy, and all-atom molecular dynamics (MD) to examine the formation process, biophysical properties, and specific lipid conformations in simulated bilayers. Experimentally, we show that liposomes containing either oxPC form SLBs by rupturing on contact with SiO₂ substrates, which differs from the typical adsorption-rupture pathway observed with nonoxidized liposomes. We also show that increasing the oxPC concentration in SLBs results in thinner bilayers that contain defects. Simulations reveal that the oxidized sn-2 tails of KDdiA-PC and KOdiA-PC bend out of the hydrophobic membrane core into the hydrophilic headgroup region and beyond. The altered conformations of these oxPC, which are affected by cholesterol content and protonation state of the oxidized functional groups, contribute to trends of decreasing membrane thickness and increasing membrane area with increasing oxPC concentration. This combined approach provides a comprehensive view of the biophysical properties of membranes containing KDdiA-PC and KOdiA-PC at the molecular level, which is crucial to understanding the role of lipid oxidation in cardiovascular disease and related immune responses.

Quantum-chemical fragmentation methods offer an attractive approach for the accurate calculation of protein-ligand interaction energies. While the molecular fractionation with conjugate caps (MFCC) scheme offers a rather straightforward approach for this purpose, its accuracy is often not sufficient. Here, we upgrade the MFCC scheme for the calculation of protein-ligand interactions by including many-body contributions. The resulting fragmentation scheme is an extension of our previously developed MFCC-MBE(2) scheme [J. Comput. Chem. 2023, 44, 1634-1644]. For a diverse test set of protein-ligand complexes, we demonstrate that by upgrading the MFCC scheme with many-body contributions, the error in protein-ligand interaction energies can be reduced significantly, and one generally achieves errors below 20 kJ/mol. Our scheme allows for systematically reducing these errors by including higher-order many-body contributions. As it combines the use of single amino acid fragments with high accuracy, our scheme provides an ideal starting point for the parametrization of accurate machine learning potentials for proteins and protein-ligand interactions.

Under confinement, the water dielectric constant is a second-order tensor with an abnormally low out-of-plane element. In our work, we investigate the dielectric tensor of an aqueous NaCl solution confined by a quartz slit-pore. The static dielectric constant is determined from local polarization density fluctuations via molecular dynamics simulations. In a pioneering investigation, we evaluate not only the effect of salinity but also surface charge. The parallel dielectric constant decreases with salinity due to dielectric saturation. From a dynamic perspective, the relaxation of water dipoles is slower within the hydration shells of ions. An anisotropic arrangement on the quartz surface results in preferred orientations of interfacial water molecules. By embedding charge, the surface structure changes, and extra dipole fluctuations in one direction may develop anisotropy in the parallel dielectric constant at the interface. Both surface charge and salinity increase the perpendicular dielectric constant. Nevertheless, the surface charge effect is more pronounced and may even recover the bulk dielectric constant value. The electric field established by the charged surface may disturb the planar hydrogen bond network at the interface, increasing out-of-plane dipolar fluctuations. Our work advances the knowledge of confined dielectric behavior, shedding light on the key role that charged surfaces play.

Molecular dynamics simulations were performed to investigate the structural and energetic features related to the direct binding of a short interfering RNA (siRNA) molecule on a silica nanoparticle functionalized with 3-aminopropyltriethoxysilane (APTES) groups, immersed in a sodium chloride aqueous solution at physiological concentration. Three different grafting densities of APTES were evaluated, namely, 2.7, 1.3, and 0.65 nm^-2. Structural features as a function of the grafting density were analyzed and characterized in terms of density field profiles, pair correlation functions, and hydrogen bonding. The analysis of the orientation of siRNA during the binding process suggested that the oligonucleotide anchors to the surface by one of their ends in a tilted arrangement and subsequently, it rotates toward a surface-parallel stabilized configuration. Free energy of binding between siRNA and the silica nanoparticle was computed using the adaptive biasing force scheme. The results indicate that the binding process is essentially barrierless and consistent with a thermodynamically spontaneous reaction, yielding the largest binding free energy, of about ∼-36 kcal/mol at the largest APTES grafting density. However, a favorable binding was also observed at the lowest APTES density (∼-16 kcal/mol). a fact that would be advantageous to facilitate the further release of siRNA within the cell.

Photoswitches are becoming increasingly popular in pharmacology due to the possibility of modifying their activity with light. Hence, it is crucial to understand the photophysics of these compounds to identify promising light-activated drugs. We focused our study on DAD, an azobenzene derivative that, according to a previous experimental investigation, can restore visual function in blind mice due to trans-cis photoisomerization upon light absorption. With the present computational study, we aim to characterize the absorption spectrum of DAD, and to understand its photoisomerization mechanism by means of conformational search analysis, quantum mechanical (QM) and hybrid QM/continuum calculations, and classical molecular dynamics simulations. Moreover, we explored the effect of the derivation (DAD vs azobenzene), the protonation (DAD vs DADH₂²⁺, the two possible protonation states) and the solvation (vacuum vs water) on the photoisomerization. Similarly to azobenzene, we showed that the photoisomerization of both protonation states of DAD begin with the population of the bright S₂ state. Then, it crosses to the S₁ surface and relaxes along the rotation of the azo dihedral to a S₁/S₀ crossing point. The latter is close to a transition state that connects the trans and cis geometries on the ground state. Finally, our results suggested that amino derivation, nonprotonation and water solvation could improve the quantum yield of the photoisomerization.

The observation of electron transfer and solvation processes in liquid-liquid multiphase systems is of great challenge, especially at the interface. In this study, the formation and spur kinetics of hydrated electrons (e_aq^-) were investigated in sodium dodecyl sulfate-water-cyclohexane-hexanol microemulsions with ω values (n_water/n_surfactant) from 18 to 48 using picosecond pulse radiolysis coupled with pulse-probe UV-vis spectroscopy. Interestingly, a relatively slow formation of e_aq^- was observed, corresponding to the electron transfer from the oil phase to water pools. The evolution curves of e_aq^- were simulated by using a simplified consecutive reaction model. It demonstrated that the electrons generated in the oil phase are solvated in the water pools of the microemulsions at a close rate. Surprisingly, the addition of NaNO₃ could accelerate electron transfer into water pools. The decays of e_aq^- in the microemulsions were significantly slower than that in pure water and accelerated with increasing water content, indicating the absence of a nanoconfinement effect.