The Journal of Physical Chemistry B最新文献

{"title":"Molecular Insights into the Penetration Enhancement Mechanism of Terpenes to Skin.","authors":"Xindong Yu, Shasha Liu, Ying Li, Shiling Yuan","doi":"10.1021/acs.jpcb.4c05910","DOIUrl":"10.1021/acs.jpcb.4c05910","url":null,"abstract":"<p><p>Terpenes are widely used in cosmetic formulations as chemical penetration enhancers (CPEs). However, the molecular mechanisms underlying the skin-penetration-enhancing effect have not been completely understood. In this work, molecular dynamics (MD) simulations were used to explore the influence of terpineol (TER), 1,8-cineole (CIN), and limonene (LIM) on the stratum corneum (SC) model. The results indicated that terpenes affected lipid membranes in a concentration-dependent manner and promoted skin permeation by disorganizing the cholesterol (CHOL) portion. The penetration of CPEs across the skin membrane also differed, with diffusion rates of limonene > 1,8-cineole > terpineol. The limonene molecules could penetrate the bilayer's center, forming a \"triple layer\" membrane structure. Furthermore, constrained simulations showed that the most favorable penetration pathway is via areas rich in CHOL. Terpineol could lower the energy barrier of the hydrophilic molecule (caffeic acid) across the cholesterol region. For the lipophilic molecule (osthole), limonene and 1,8-cineole could reduce the energy barrier across the cholesterol region. Each of the results provides novel insights into the mechanism of penetration of CPEs in the skin.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"12507-12516"},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Mechanistic Analysis of Liquid-Crystalline Polymers Composed of <i>p</i>-Hydroxybenzoic Acid I: Thermal Properties.","authors":"Kazushi Fujimoto, Hiroaki Ishikawa, Minoru Shimooka, Toshihiro Kaneko, Susumu Okazaki","doi":"10.1021/acs.jpcb.4c06169","DOIUrl":"https://doi.org/10.1021/acs.jpcb.4c06169","url":null,"abstract":"<p><p>All-atom molecular dynamics (MD) calculations of the crystalline polymeric <i>p</i>-hydroxybenzoic acid (<i>p</i>HBA) were conducted at various temperatures to investigate its thermal response. The calculated structure factor equivalent to the X-ray diffraction pattern of <i>p</i>HBA clearly showed two phase transitions occurring at 600 and 650 K. The first transition at 600 K occurred from the orthorhombic phase to the pseudohexagonal phase, identified by the presence of the 211-peak. This peak disappeared during the second transition at 650 K, indicating that the phase at 650 K was hexagonal. The structure of the pseudohexagonal phase was anisotropic with respect to the <i>ab</i> plane but isotropic in the hexagonal phase. Discontinuous changes in the calculated unit cell volume and unit cell length were observed at 600 K, associated with the first phase transition. We also calculated the linear expansion coefficients in three directions. An anisotropic expansion was observed in three directions for the orthorhombic crystal. In particular, the linear expansion coefficient in the <i>c</i>-direction was negative. In contrast to this, an isotropic expansion was found in the <i>a</i>- and <i>b</i>-directions for the hexagonal crystal, while the expansion in the <i>c</i>-direction is still negative. This study provides valuable insights into the thermal behavior of polymeric <i>p</i>HBA, which is essential for understanding its structural transformations and designing crystalline polymers with tailored thermal properties.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Computational Approach to Modeling Excitation Energy Transfer and Quenching in Light-Harvesting Complexes.","authors":"Chris John, Laura Pedraza-González, Elena Betti, Lorenzo Cupellini, Benedetta Mennucci","doi":"10.1021/acs.jpcb.4c06617","DOIUrl":"https://doi.org/10.1021/acs.jpcb.4c06617","url":null,"abstract":"<p><p>Light-harvesting complexes (LHCs) play a critical role in modulating energy flux within photosynthetic organisms in response to fluctuating light. Under high light conditions, they activate quenching mechanisms to mitigate photodamage. Despite their importance, the molecular mechanisms underlying these photoprotective processes remain incomplete. Herein, we present a computational protocol to model the energy pathways in the LHC, focusing specifically on the minor CP29 antenna complex of plants. We explore the factors that modulate the switch between the light-harvesting and quenched states. The protocol includes modeling the exciton Hamiltonian of the chlorophylls/lutein aggregate and calculating population dynamics using a kinetic model based on the Redfield-Förster approach. Our analysis reveals a highly tunable excited-state lifetime for the complex, that can switch between quenched and unquenched state depending on the excitation energy of the lutein, which acts as a final quencher, in accordance with recent experiments. Moreover, we observe that the s-<i>trans</i> lutein conformers are more likely to exhibit characteristics of the quencher.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Furopyridine Derivatives as Potent Inhibitors of the Wild Type, L858R/T790M, and L858R/T790M/C797S EGFR.","authors":"Duangjai Todsaporn, Alexander Zubenko, Victor G Kartsev, Panupong Mahalapbutr, Athina Geronikaki, Samvel N Sirakanyan, Lyudmila N Divaeva, Victoria Chekrisheva, Ilkay Yildiz, Kiattawee Choowongkomon, Thanyada Rungrotmongkol","doi":"10.1021/acs.jpcb.4c06246","DOIUrl":"10.1021/acs.jpcb.4c06246","url":null,"abstract":"<p><p>The treatment of patients with nonsmall cell lung cancer (NSCLC) using epidermal growth factor receptor (EGFR) inhibitors is complicated by drug-sensitive activating L858R/T790M and L858R/T790M/C797S mutations. To overcome drug resistance, a series of furopyridine (PD) compounds were virtually screened to identify potent EGFR inhibitors using molecular docking and molecular dynamics (MD) simulations based on the solvated interaction energy (SIE) method. Several PD compounds identified from virtual screening demonstrated the potential to suppress both wild-type and mutant forms of EGFR, with IC₅₀ values in the nanomolar range. Among these, <b>PD18</b> and <b>PD56</b> exhibited highly potent inhibitory activity against both wild-type and mutant forms of EGFR, surpassing the efficacy of known drugs. Additionally, both PD compounds were cytotoxic to NSCLC cell lines (A549 and H1975) while being nontoxic to normal cell lines (Vero). The interaction mechanisms of both PD compounds complexed with wild-type and mutant forms of EGFR were elucidated through 500 ns molecular dynamics simulations. The predicted binding affinity from molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) correlated well with the experimental binding affinity derived from IC₅₀ values. Furthermore, it was observed that van der Waals interactions, rather than electrostatic interactions, played a significant role in interacting with EGFR's active site. The strong inhibitory activity against EGFR was attributed to two key residues, M793 and S797, via hydrogen bonding, corresponding with lower solvent accessibility and a higher number of atomic contacts. Therefore, these potent compounds could be developed as promising drugs targeting both wild-type and mutant EGFR for the treatment of NSCLC.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"12389-12402"},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Probing the Conformational Ensemble of the Amyloid Beta 16-22 Fragment with Parallel-Bias Metadynamics.","authors":"Timur Magsumov, Ilya Ibraev, Igor Sedov","doi":"10.1021/acs.jpcb.4c04919","DOIUrl":"10.1021/acs.jpcb.4c04919","url":null,"abstract":"<p><p>Aβ(16-22) is a segment of the Alzheimer's-related β-amyloid peptide that plays a crucial role in its aggregation. This study applies well-tempered parallel-bias metadynamics to investigate the impact of several denaturants and osmolytes on the conformational ensembles of both termini-capped and uncapped Aβ(16-22) monomers. Comparison of the different sets of collective variables in the metadynamics bias shows that using the set of backbone torsional angles results in better and faster convergence of simulations than employing more general structural characteristics of the short peptide. The equilibrium conformational ensembles of the peptides are characterized in pure water and in the presence of TMAO, urea, guanidinium chloride, and trifluoroethanol. In particular, trifluoroethanol and TMAO are found to increase the population of compact peptide conformations, whereas urea and guanidinium chloride favor extended structures. The analysis of the free energy surfaces in the presence of various substances with a comparison of the behavior of the capped and uncapped peptide forms reveals the role of different types of intrapeptide interactions such as salt bridges, hydrophobic contacts, and hydrogen bonds in stabilization of the compact or extended structures. As compounds reducing the abundance of the compact states of Aβ(16-22) and other disordered peptides are likely to suppress their amyloid fibril formation, simulations in the systems with this short peptide may be useful for the virtual screening of such compounds.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"12333-12347"},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Density Differences' Effect on Phase Transition Kinetics.","authors":"Kati Avramova, Alexander Karamanov","doi":"10.1021/acs.jpcb.4c04898","DOIUrl":"10.1021/acs.jpcb.4c04898","url":null,"abstract":"<p><p>In this theoretical study, we investigate the impact of density differences between the growing new phase and the parent phase on the overall transformation degree. By extending Kolmogorov's formalism, we derive an expression for the overall volume transformation degree, which becomes relevant when density differences are not negligible. We demonstrate that the volume and mass transformation degrees differ in the presence of density differences and provide an expression for the mass transformation degree.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"12571-12577"},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Exogenous Glucose on Molecular Transport through Bacterial Membranes Studied by Second Harmonic Light Scattering.","authors":"Xiao-Hua Hu, Yujie Li, Tong Wu, Jianqiang Ma, Yuhao Wu, Michael J Wilhelm, Hai-Lung Dai","doi":"10.1021/acs.jpcb.4c06134","DOIUrl":"10.1021/acs.jpcb.4c06134","url":null,"abstract":"<p><p>Recent studies revealed that exogenous glucose increases the efficacy of aminoglycosides in eliminating bacterial persister cells. It was speculated that this increased antimicrobial efficacy is induced by glucose-facilitated uptake of the antibiotics. Here, we examine this hypothesis by using second-harmonic light scattering to time-resolve the transport of an antimicrobial quaternary ammonium compound (QAC), malachite green, across the membranes of living <i>Escherichia coli</i> (<i>E. coli</i>) in the presence of glucose. The results show that when the glucose concentration increased from 0 to 100 μM, the QAC transport rate constant across the cytoplasmic membrane of <i>E. coli</i> increased by 3.6 times. Further increase of glucose concentration into the millimolar range, however, does not further enhance the transport rate constant. Conversely, a study of QAC transport across the protein-free membrane of liposomes (constructed from the polar lipid extract of <i>E. coli</i>) indicates that the glucose-induced enhancement in membrane transport in <i>E. coli</i> is mediated by protein transporters. Cell viability experiments show that low concentration of exogenous glucose enhances the QAC efficacy in eliminating <i>E. coli</i>. The loss of viability of the bacterial cells in the presence of the QAC at minimum inhibitory concentration increased dramatically when glucose concentration increased from 0 to 100 μM but increasing the glucose concentration up to 1 mM did not further enhance the antimicrobial efficacy. This behavior coincides with the observed increase in QAC transport rate constant as a function of glucose concentration. These observations reveal a novel antimicrobial strategy in which low concentration glucose enhances the uptake of antimicrobials into the bacteria, thereby improving antimicrobial efficacy.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"12379-12388"},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protocols for Metallo- and Serine-β-Lactamase Free Energy Predictions: Insights from Cross-Class Inhibitors.","authors":"J Jasmin Güven, Marko Hanževački, Papu Kalita, Adrian J Mulholland, Antonia S J S Mey","doi":"10.1021/acs.jpcb.4c06379","DOIUrl":"10.1021/acs.jpcb.4c06379","url":null,"abstract":"<p><p>While relative binding free energy (RBFE) calculations using alchemical methods are routinely carried out for many pharmaceutically relevant protein targets, challenges remain. For example, open-source tools do not support the easy setup and simulation of metalloproteins, particularly when ligands directly coordinate to the metal site. Here, we evaluate the performance of RBFE methods for KPC-2, a serine-β-lactamase (SBL), and two nonbonded metal parameter setups for VIM-2, a metallo-β-lactamase (MBL) with two active site zinc ions. We tested two different ways of modeling the ligand-zinc interactions. First, a restraint-based approach, in which FF14SB zinc parameters are combined with harmonic restraints between the zincs and their coordinating residues. The second approach uses an upgraded Amber force field (UAFF) for zinc-metalloproteins with adjusted partial charges and nonbonded terms of zinc-coordinating residues. Molecular mechanics (MM) and quantum mechanics/molecular mechanics (QM/MM) simulations show that the crystallographically observed zinc coordination is not retained in MM simulations with either zinc parameter set for a series of known phosphonic acid-based inhibitors bound to VIM-2. These phosphonic acid-based inhibitors exhibit known cross-class affinity for SBLs and MBLs and serve as a benchmark for RBFE calculations for VIM-2, after validation with KPC-2. The KPC-2 free energy of binding estimates are within expected literature accuracies for the ligand series with a mean absolute error of <math><msubsup><mrow><mn>0.45</mn></mrow><mrow><mn>0.28</mn></mrow><mrow><mn>0.66</mn></mrow></msubsup></math> kcal/mol and a Pearson's correlation coefficient of <math><msubsup><mrow><mn>0.93</mn></mrow><mrow><mn>0.85</mn></mrow><mrow><mn>0.98</mn></mrow></msubsup></math>. For VIM-2, the UAFF approach has improved correlation from <math><msubsup><mrow><mn>0.55</mn></mrow><mrow><mrow><mo>-</mo></mrow><mrow><mn>0.04</mn></mrow></mrow><mrow><mn>0.88</mn></mrow></msubsup></math> to <math><msubsup><mrow><mn>0.78</mn></mrow><mrow><mn>0.38</mn></mrow><mrow><mn>0.92</mn></mrow></msubsup></math>, compared to the restraint approach. The presented strategies for handling ligands coordinating to metal sites highlight that simple metal parameter models can provide some predictive free energy estimates for metalloprotein-ligand systems, but leave room for improvement in their ease of use, modeling of coordination sites and as a result, their accuracy.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"12416-12424"},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Self-Consistent Molecular Mechanism of β₂-Microglobulin Aggregation.","authors":"Vaishnavi Tammara, Atanu Das","doi":"10.1021/acs.jpcb.4c06611","DOIUrl":"10.1021/acs.jpcb.4c06611","url":null,"abstract":"<p><p>Despite the consensus on the origin of dialysis-related amyloidosis (DRA) being β₂-microglobulin (β₂m) aggregation, the debate on the underlying mechanism persists because of the continuous emergence of β₂m variant- and pH-dependent contradictory results. By characterizing the native monomeric (initiation) and aggregated fibrillar (termination) states of β₂m via a combination of two enhanced sampling approaches, we here propose a mechanism that explains the heterogeneous behavior of wild-type (WT) and pathogenic (V27M and D76N) β₂m variants in physiological and disease-pertinent acidic pH environments. It appears that the higher retainment of monomeric native folds at neutral pH (native-like) distinguishes pathogenic β₂m mutants from the WT (moderate loss). However, at acidic pH, all three variants behave similarly in producing a substantial amount of partially unfolded states (conformational switch, propensity), though with different extents (WT < V27M < D76N). Whereas at the fibrillar end, all β₂m variants display a pH-dependent protofilament separation pathway and a higher protofilament binding affinity (stability) at acidic pH, where the relative order of binding affinity (WT < V27M < D76N) remains consistent with pH modulation. Combining these observations, we conclude that β₂m variants possibly shift from native-like aggregation to conformational switch-initiated fibrillation as the pH is altered from neutral to acidic. The combined propensity-stability approach based on the initiation and termination points of β₂m aggregation not only assists us in deciphering the mechanism but also emphasizes the protagonistic roles of both terminal points in the overall aggregation process.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"12425-12442"},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biliverdin's Propionic Chains Influence Oligomerization in Sandercyanin.","authors":"Eleftherios Mainas, Gregory M Curtin, Shaena D Riddles, Elisa Pieri","doi":"10.1021/acs.jpcb.4c06722","DOIUrl":"10.1021/acs.jpcb.4c06722","url":null,"abstract":"<p><p>Sandercyanin is a mildly fluorescent biliprotein with a large Stokes shift, a tetrameric quaternary structure, and a biliverdin (BV) chromophore that does not covalently bond to the protein. To adapt this promising protein for use in bioimaging, it is necessary to produce monomeric mutants that retain the spectroscopic properties while increasing the fluorescence quantum yield. Modulating these properties through the protonation state of BV's propionic tails is a possible avenue, if detailed mechanistic information on the role of such chains becomes available. In this study, we use a microstate model for the titration process of BV and couple it with constant pH molecular dynamics to study protonation states in the apo protein, the artificial monomer, and the tetramer and identify shifts. Our results indicate that several residues might have a central role in oligomerization as a response to the presence of BV and especially to the protonation state of the propionic tails. While the absorption properties are not strongly impacted by the tails, their protonation state has an impact on the chromophore geometry, which likely influences the fluorescence.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"12443-12455"},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}