The Journal of Physical Chemistry B最新文献

Fluorine is an element renowned for its unique properties. Its powerful capability to modulate molecular properties makes it an attractive substituent for protein binding ligands; however, the rational design of fluorination can be challenging with effects on interactions and binding energies being difficult to predict. In this Perspective, we highlight how computational methods help us to understand the role of fluorine in protein–ligand binding with a focus on molecular simulation. We underline the importance of an accurate force field, present fluoride channels as a showcase for biomolecular interactions with fluorine, and discuss fluorine specific interactions like the ability to form hydrogen bonds and interactions with aryl groups. We put special emphasis on the disruption of water networks and entropic effects.

Molecular dynamics (MD) is a great tool for elucidating conformational dynamics of proteins and peptides in water at the atomistic level that often surpasses the level of detail available experimentally. Structure predictions, however, are limited by the accuracy of the underlying MD force field. This limitation is particularly stark in the case of intrinsically disordered peptides and proteins, which are characterized by solvent-accessible and disordered peptide regions and domains. Recent studies show that most additive MD force fields, including CHARMM36m, do not reproduce the intrinsic conformational distributions of guest amino acid residues x in cationic GxG peptides in water in line with experimental data. Positing that a lack of polarizability in additive MD force fields may be the culprit for the reported discrepancies, we here examine the conformational dynamics of guest glycine and alanine residues in cationic GxG peptides in water using two polarizable MD force fields, CHARMM Drude and AMOEBA. Our results indicate that while AMOEBA captures the experimental data better than CHARMM Drude, neither of the two polarizable force fields offers an improvement of the Ramachandran distributions of glycine and alanine residues in cationic GGG and GAG peptides, respectively, over CHARMM36m.

The G protein-coupled receptors (GPCRs) play a pivotal role in numerous biological processes as crucial cell membrane receptors. However, the dynamic mechanisms underlying the activation of GPR183, a specific GPCR, remain largely elusive. To address this, we employed computational simulation techniques to elucidate the activation process and key events associated with GPR183, including conformational changes from inactive to active state, binding interactions with the G_i protein complex, and GDP release. Our findings demonstrate that the association between GPR183 and the G_i protein involves the formation of receptor-specific conformations, the gradual proximity of the G_i protein to the binding pocket, and fine adjustments of the protein conformation, ultimately leading to a stable GPR183-G_i complex characterized by a high energy barrier. The presence of G_i protein partially promotes GPR183 activation, which is consistent with the observation of GPCR constitutive activity test experiments, thus illustrating the reliability of our calculations. Moreover, our study suggests the existence of a stable partially activated state preceding complete activation, providing novel avenues for future investigations. In addition, the relevance of GPR183 for various diseases, such as colitis, the response of eosinophils to Mycobacterium tuberculosis infection, antiviral properties, and pulmonary inflammation, has been emphasized, underscoring its therapeutic potential. Consequently, understanding the activation process of GPR183 through molecular dynamic simulations offers valuable kinetic insights that can aid in the development of targeted therapies.

The isatin group is widespread in nature and is considered to be a privileged building block for drug discovery. In order to develop novel SHP1 inhibitors with fluorescent properties as tools for SHP1 biology research, this work designed and synthesized a series of isatin derivatives. The presentive compound 5a showed good inhibitory activity against SHP1^PTP with IC₅₀ of 11 ± 3 μM, displayed about 92% inhibitory rate against MV-4-11 cell proliferation at the concentration of 20 μM, exhibited suitable fluorescent properties with a long emission wavelength and a large Stokes shift, and presented blue fluorescent imaging in HeLa cells with low cytotoxicity. This study could offer chemical tool to further understand SHP1 biology and develop novel SHP1 inhibitors in therapy.

Predicting the binding poses of docking with an accurate estimation of binding energies is highly important but very challenging in computational drug design. A quantum mechanics (QM) calculation-based docking approach considering multiple conformations and orientations of the ligand is introduced here to tackle the problem. This QM docking consists of three steps: generating an ensemble of binding poses with a conventional docking simulation, computing the binding energies with self-consistent charge density functional theory tightly binding with dispersion correction (DFTB-D) to selecting the 10 top binding modes, and optimizing the selected binding mode structures using the ONIOM(DFTB:PM7) technique to determine the binding poses. The ONIOM(DFTB-D:PM6) docking approach is tested on 121 ligand–receptor biocomplexes with the crystal structures obtained from the Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB). The result shows that the new method is highly satisfactory for the accurate prediction of the binding poses. The new docking method should be beneficial to structure-based drug design.

Retinylidene conformations and rearrangements of the hydrogen-bond network in the vicinity of the protonated Schiff base (PSB) play a key role in the proton transfer process in the Heliorhodopsin photocycle. Photoisomerization of the retinylidene chromophore and the formation of photoproducts corresponding to the early intermediates were modeled using a combination of molecular dynamics simulations and quantum mechanical/molecular mechanics calculations. The resulting structures were refined, and the respective excitation energies were calculated. Aided by metadynamics simulations, we constructed a photoisomerized intermediate where the 13-cis retinylidene chromophore is rotated about a parallel pair of double bonds at C13=C14 and C15=N_Z double bonds. We demonstrate how the deprotonation of the Schiff base and the concomitant protonation of the Glu107 counterion are only favored because of these rearrangements.

GENeralized-Ensemble SImulation System (GENESIS) is a molecular dynamics (MD) software developed to simulate the conformational dynamics of a single biomolecule, as well as molecular interactions in large biomolecular assemblies and between multiple biomolecules in cellular environments. To achieve the latter purpose, the earlier versions of GENESIS emphasized high performance in atomistic MD simulations on massively parallel supercomputers, with or without graphics processing units (GPUs). Here, we implemented multiscale MD simulations that include atomistic, coarse-grained, and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. They demonstrate high performance and are integrated with enhanced conformational sampling algorithms and free-energy calculations without using external programs except for the QM programs. In this article, we review new functions, molecular models, and other essential features in GENESIS version 2.1 and discuss ongoing developments for future releases.

The guanine-rich telomeric repeats can form G-quadruplexes (G4s) that alter the accessibility of the single-stranded telomeric overhang. In this study, we investigated the effects of Na⁺ and K⁺ on G4 folding and accessibility through cation introduction and exchange. We combined differential scanning calorimetry (DSC), circular dichroism (CD), and single molecule Förster resonance energy transfer (smFRET) to monitor the stability, conformational dynamics, and complementary strand binding accessibility of G4 formed by single-stranded telomeric DNA. Our data showed that G4 formed through heating and slow cooling in K⁺ solution exhibited fewer conformational dynamics than G4 formed in Na⁺ solution, which is consistent with the higher thermal stability of G4 in K⁺. Monitoring cation exchange with real time smFRET at room temperature shows that Na⁺ and K⁺ can replace each other in G4. When encountering high K⁺ at room or body temperature, G4 undergoes a slow conformational rearrangement process which is mostly complete by 2 h. The slow conformational rearrangement ends with a stable G4 that is unable to be unfolded by a complementary strand. This study provides new insights into the accessibility of G4 forming sequences at different time points after introduction to a high K⁺ environment in cells, which may affect how the nascent telomeric overhang interacts with proteins and telomerase.

Due to their many attractive physicochemical properties, ionic liquids (ILs) have received extensive attention with numerous applications proposed in various fields of science and technology. Despite this, the molecular origins of many of their properties, such as the moisture absorption capability, are still not well understood. For insight into this, we systematically synthesized 24 types of ILs by the combination of the dimethyl phosphate anion with various types of alkyl group-substituted cyclic cations─imidazolium, pyrazolium, 1,2,3-triazolium, and 1,2,4-triazolium cations─and performed a detailed analysis of the dehumidification properties of these ILs and their aqueous solutions. It was found that these IL systems have a high dehumidification capability (DC). Among the monocationic ILs, the best performance was obtained with 1-cyclohexylmethyl-4-methyl-1,2,4-triazolium dimethyl phosphate, whose DC (per mol) value is 14 times higher than that of popular solid desiccants like CaCl₂ and silica gel. Dicationic ILs, such as 1,1′-(propane-1,3-diyl)bis(4-methyl-1,2,4-triazolium) bis(dimethyl phosphate), showed an even better moisture absorption, with a DC (per mol) value about 20 times higher than that of CaCl₂. Small- and wide-angle X-ray scattering measurements of eight types of 1,2,4-triazolium dimethyl phosphate ILs were performed and revealed that the majority of these ILs form nanostructures. Such nanostructures, which vary with the identity of the IL and the water content, fall into three main categories: bicontinuous microemulsions, hexagonal cylinders, and micelle-like structures. Water in the solutions exists primarily in polar regions in the nanostructures; these spaces function as water pockets at relatively low water concentrations. Since the structure and stability of the aggregated forms of the ILs are mainly governed by the interactions of nonpolar groups, the alkyl side chains of the cations play an important role in the DC and temperature-dependent equilibrium water vapor pressure of the IL solutions. Our experimental findings and molecular dynamics simulation results shed light on the moisture absorption mechanism of the IL aqueous solutions from a molecular perspective.

High-temperature polymer electrolyte membrane fuel cells (HT-PEMFCs) are gaining more and more attention due to their higher efficiency than low-temperature ones. Polybenzimidazole (PBI) membranes are the most popular membranes used in HT-PEMFCs. However, their chemical stability and chemical degradation mechanisms, which directly affect the lifetime of fuel cells, have been hardly reported. We applied the density functional theory and used ABPBI as an example membrane to investigate the chemical degradation mechanisms of PBI membranes. The possible degradation mechanisms that occurred on eight sites have been proposed, where sites 2 and 3 located on the phenyl ring are determined as two weak sites toward OH radical and oxygen molecule attack. When the terminal is the H atom at site 7, it is also weak under OH radical attack. Regarding these, the substituent effect on the chemical stability of polymers has been studied. By introducing four –C₂F₅ or –CN groups, the barrier heights of the corresponding degradation reactions are increased; thus, the chemical stabilities of related membranes are improved. The selection of terminal atoms was also explored for alleviating the chemical degradation of the membrane. The investigated proton transfer properties of nine model compounds revealed that introducing four –C₂F₅ or –CN groups improves the proton dissociation properties occurring at the cathode. The increase of phosphoric acid concentration is helpful for the proton transfer at both the membrane and the cathode. This work may hopefully help the design and synthesis of HT-PEMFCs with good stability and high efficiency.