The Journal of Physical Chemistry B最新文献

{"title":"All-Atom Perspective of the DENV-3 Methyltransferase Inhibition Mechanism.","authors":"Xiao Liu, Kaiwen Pang, Hangfei Wu, Xiaohui Wang, John Z H Zhang, Zhaoxi Sun","doi":"10.1021/acs.jpcb.4c05943","DOIUrl":"10.1021/acs.jpcb.4c05943","url":null,"abstract":"<p><p>The Dengue virus (DENV) is an enveloped, single-stranded RNA virus with several antigenically distinct serotypes (DENV-1 to DENV-5). Dengue fever, as a major public health threat transmitted by mosquitoes, affects millions of people worldwide (especially in tropical and subtropical regions). Toward drug developments of DENV, the nonstructural protein 5 methyltransferase (MTase) serves as an attractive target. The MTase transforms <i>S</i>-adenosyl methionine to <i>S</i>-adenosyl homocysteine (SAH), which is thereby selected as the target with which external drugs compete with. In this work, using alanine scanning with generalized Born and interaction entropy (ASGB-IE), we provide an all-atom perspective of the protein-ligand interactions formed by DENV-3 MTase and SAH derivatives. Residues with consistently high contributions to stabilization are summarized, and the general DENV-3 MTase inhibition mechanism is elucidated. Additionally, the mutational impact on binding thermodynamics is found to be entropy-driven. We also highlight the advantage of the ASGB-IE method for affinity estimation compared to standard end-point protocols, which is highly related to the selection of interfacial residues in free energy estimation. Finally, we performed a thorough scan of the mutational space on critical sites (saturation mutagenesis) and identified 14 mutants causing resistance to the current inhibitors.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"12358-12367"},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783373","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":"Organophosphate Hydrolysis by a Designed Metalloenzyme: Impact of Mutations Explained.","authors":"Edyta Dyguda-Kazimierowicz, Wiktoria Jedwabny","doi":"10.1021/acs.jpcb.4c06809","DOIUrl":"10.1021/acs.jpcb.4c06809","url":null,"abstract":"<p><p>The efficient design of novel enzymes has been attainable only by a combination of theoretical approaches and experimental refinement, suggesting inadequate performance of de novo design protocols. Based on the analysis of the evolutionary trajectory of a designed organophosphate hydrolase, this work aimed at developing and validating the improved theoretical models describing the catalytic activity of five enzyme variants (including wild-type as well as theoretically derived and experimentally refined enzymes) performing the hydrolysis of diethyl 7-hydroxycoumarinyl phosphate. The following aspects possibly important for enzyme design were addressed: the level of theory sufficient for a reliable description of enzyme-reactant interactions, the issue of ground state (GS) destabilization versus transition state (TS) stabilization, and the derivation of the proper side chain rotamers of amino acid residues. For enzyme variants analyzed herein, differential transition state stabilization (DTSS, i.e., preferential TS binding by an enzyme over the GS binding) calculated with a non-empirical model of the interaction energy (i.e., multipole electrostatic plus approximate dispersion terms, MED) displayed a superior performance in ranking the enzyme catalytic activity. The MED DTSS-based systematic rotamer refinement performed with an efficient scanning procedure and accounting for long-range interaction energy terms is an important step capable of unlocking the full potential impact of the given residue that could be otherwise overlooked with a conventional static approach featuring optimization to the nearby minimum. While TS stabilization is the main factor contributing to the increased catalytic activity of the de novo-designed variant studied in this work, directed evolution refinement appears to impact the catalytic activity of another enzyme variant analyzed herein via GS destabilization.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"12456-12470"},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794052","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":"Impact of Intracellular Proteins on μ-Opioid Receptor Structure and Ligand Binding.","authors":"Caitlin E Scott, Leah A Juechter, Josephine Rocha, Lauren D Jones, Brenna Outten, Taylor D Aishman, Alaina R Ivers, George C Shields","doi":"10.1021/acs.jpcb.4c05214","DOIUrl":"https://doi.org/10.1021/acs.jpcb.4c05214","url":null,"abstract":"<p><p>Chronic pain is a prevalent problem affecting approximately one out of every five adults in the U.S. The most effective way to treat chronic pain is with opioids, but they cause dangerous side effects such as tolerance, addiction, and respiratory depression, which makes them quite deadly. Opioids, such as fentanyl, target the μ-opioid receptor (MOR), which can then bind to the intracellular G_i protein or the β-arrestin protein. The G_i pathway is primarily responsible for pain relief and potential side effects, but the β-arrestin pathway is chiefly responsible for the unwanted side effects. Ideally, an effective pain medication without side effects would bind to MOR, which would bias signaling solely through the G_i pathway. We used the Bio3D library to conduct principal component analysis to compare the cryo-electron microscopy MOR structures in complex with the G_i versus an X-ray crystallography MOR structure with a nanobody acting as a G_i mimic. Our results agree with a previous study by Munro, which concluded that nanobody-bound MOR is structurally different than G_i-bound MOR. Furthermore, we investigated the structural diversity of opioids that can bind to MOR. Quantum mechanical calculations show that the low energy solution structures of fentanyl differ from the one bound to MOR in the experimental structure, and p<i>K</i>_a calculations reveal that fentanyl is protonated in aqueous solution. Glide docking studies show that higher energy structures of fentanyl in solution form favorable docking complexes with MOR. Our calculations show the relative abundance of each fentanyl conformation in solution as well as the energetic barriers that need to be overcome to bind to MOR. Docking studies confirm that multiple fentanyl conformations can bind to the receptor. Perhaps a variety of conformations of fentanyl can stabilize multiple conformations of the MOR, which can explain why fentanyl can induce different intracellular signaling and multiple physiological effects.</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":"142851662","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":"Rheology of Ring Copolymers in Dilute Solutions.","authors":"Sumit Kumar, Parbati Biswas","doi":"10.1021/acs.jpcb.4c05788","DOIUrl":"https://doi.org/10.1021/acs.jpcb.4c05788","url":null,"abstract":"<p><p>We investigate the rheology of ring copolymers theoretically within the framework of the optimized Rouse-Zimm theory in dilute solutions. The ring copolymer is composed of two type of monomers (A and B) of different sizes (A < B), which is represented by unequal-sized beads connected via harmonic springs with different spring constants. The hydrodynamic interactions (HI) between the monomers is modeled using the preaveraged HI tensor. These interactions accelerate the collective relaxation modes and impede the local relaxation modes. In the presence of HI, the storage modulus shows a quasi-plateau regime, demonstrating a viscoelastic solid-like response of the polymer, while the loss modulus exhibits a bimodal pattern due to the difference in the mobilities of the monomers. The inverse of the crossover frequency represents the overall characteristic relaxation time, which is higher for the ring copolymers than for the Rouse rings, suggesting a slower relaxation of the ring copolymers due to the presence of relatively large sized monomers. The quasi-plateau in the storage modulus and the bimodality in the loss modulus are enhanced with an increase in the size and number fraction of B-type monomers. An increase in the size of the B-type monomers increases both storage and loss moduli, resulting in an overall decrease in the dynamics of the ring copolymers.</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":"142851671","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":"Multiscale Elasticity of Epoxy Networks by Rheology and Brillouin Light Spectroscopy.","authors":"Emmanouela Filippidi, Anuj K Dhiman, Benke Li, Thanasis Athanasiou, Dimitris Vlassopoulos, George Fytas","doi":"10.1021/acs.jpcb.4c06492","DOIUrl":"10.1021/acs.jpcb.4c06492","url":null,"abstract":"<p><p>The response of soft materials to an imposed oscillatory stress is typically frequency dependent, with the most utilized frequency range falling in the range of 10^-2-10² rad/s. In contrast to most conventional contact techniques for measuring material elasticity, like tensile or shear rheology and atomic force microscopy, or invasive techniques using probes, such as microrheology, Brillouin light spectroscopy (BLS) offers an optical, noncontact, label-free, submicron resolution and three-dimensional (3D) mapping approach to access the mechanical moduli at GHz frequencies. Currently, the correlation between the experimental viscoelastic (at lower frequencies) and elastic (at higher frequencies) moduli has fundamental and practical relevance, but remains unclear. We utilize a series of solvent-free epoxy polymer networks with variable cross-link density as models to compare the storage modulus, <i>G</i>', (in the MPa range) obtained from shear rheology and the longitudinal modulus, <i>M</i>', (in the GPa range) extracted from BLS. Our results show that <i>G</i>' exhibits a much stronger increase with increasing cross-link density than <i>M</i>' (by a factor of about 3.5). This finding is discussed in the context of the phantom network model for <i>G</i>' and Wood's inverse rule of mixtures for <i>M</i>'. The epoxy polymer network displays an unexpectedly fast hypersonic dispersion compared to its uncross-linked precursor. These results testify the importance of obtaining reliable information about the elasticity of networks and will hopefully trigger further investigations in the direction of bridging the elasticity of soft materials at different scales.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"12628-12637"},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764553","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":"Structure of Ion Pair Receptor Combined with Li⁺Cl^- in Concentrated Acetonitrile Solutions Studied by Neutron Diffraction with ⁶Li/⁷Li Isotopic Substitution Method.","authors":"Yasuo Kameda, Tsubasa Mimuro, Shin-Ichi Kondo, Takashi Honda, Toshiya Otomo","doi":"10.1021/acs.jpcb.4c06139","DOIUrl":"10.1021/acs.jpcb.4c06139","url":null,"abstract":"<p><p>Neutron diffraction measurements with the ⁶Li/⁷Li isotopic substitution method have been carried out to obtain direct structural information on the ion pair receptor, C₁₆H₃₄O₄N₄, combined with Li⁺Cl^- ion pair in concentrated acetonitrile solutions. The difference interference term, Δ_Li(<i>Q</i>), was derived from the difference between the total interference term observed for ⁶Li- and ⁷Li-enriched sample solutions. Structural parameters concerning the Li⁺Cl^--receptor complex were determined by the least-squares fitting analysis of the observed Δ_Li(<i>Q</i>). It has been found that the Li⁺ forms bonds with two ether-oxygen atoms of the receptor molecule with the distances of <i>r</i>(Li⁺···O) = 1.88(4) and 1.9(1) Å and simultaneously one Cl^- and one N atom of a CD₃CN molecule in concentrated 12 and 7 mol % LiCl-receptor solutions in CD₃CN, respectively.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"12533-12539"},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778804","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 Alkyl Chain Length on the Magnitude of Dynamically Correlated Molecules and Dynamical Crossover in Alkyltriethylammonium-Based Ionic Liquids.","authors":"Beibei Yao, Marian Paluch, Zaneta Wojnarowska, Danuta Kruk","doi":"10.1021/acs.jpcb.4c05070","DOIUrl":"10.1021/acs.jpcb.4c05070","url":null,"abstract":"<p><p>This study explores the impact of alkyl chain length on dynamic heterogeneity and dynamic crossover in alkyltriethylammonium-based ionic liquids ([TEA-R][TFSI]) with varying alkyl chain lengths (R = C6, C8, and C10). Using differential scanning calorimetry and broadband dielectric spectroscopy, we observed that these ionic liquids are excellent glassformers with notable ionic conductivity at room temperature. Furthermore, the number of dynamically correlated molecules at the glass transition temperature, reflecting the dynamic heterogeneity, is exceptionally small for TEA-R ILs and becomes more reduced with longer alkyl chains. Moreover, the temperature dependence of conductivity requires two Vogel-Fulcher-Tammann equations with distinct sets of fitting parameters for an accurate description. The crossover temperature <i>T</i>_b, indicating the transition to complex dynamics, increases with the alkyl chain length.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"12578-12585"},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783376","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":"Resonant Soft X-ray Scattering Reveals the Distribution of Dopants in Semicrystalline Conjugated Polymers.","authors":"Phong H Nguyen, Devon Callan, Evan Plunkett, Max Gruschka, Nima Alizadeh, Matthew R Landsman, Gregory M Su, Eliot Gann, Christopher M Bates, Dean M DeLongchamp, Michael L Chabinyc","doi":"10.1021/acs.jpcb.4c05774","DOIUrl":"10.1021/acs.jpcb.4c05774","url":null,"abstract":"<p><p>The distribution of counterions and dopants within electrically doped semicrystalline conjugated polymers, such as poly(3-hexylthiophene-2,5-diyl) (P3HT), plays a pivotal role in charge transport. The distribution of counterions in doped films of P3HT with controlled crystallinity was examined using polarized resonant soft X-ray scattering (P-RSoXS). The changes in scattering of doped P3HT films containing trifluoromethanesulfonimide (TFSI^-) and 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F₄TCNQ^•-) as counterions to the charge carriers revealed distinct differences in their nanostructure. The scattering anisotropy of P-RSoXS from doped blends of P3HT was examined as a function of the soft X-ray absorption edge and found to vary systematically with the composition of crystalline and amorphous domains and by the identity of the counterion. A computational methodology was developed and used to simulate the soft X-ray scattering as a function of morphology and molecular orientation of the counterions. Modeling of the P-RSoXS at N and F K-edges was consistent with a structure where the conjugated plane of F₄TCNQ^•- aligns perpendicularly to that of the P3HT backbone in ordered domains. In contrast, TFSI^- was distributed more uniformly between domains with no significant molecular alignment. The approach developed here demonstrates the capabilities of P-RSoXS in identifying orientation, structural, and compositional distributions within doped conjugated polymers using a computational workflow that is broadly extendable to other soft matter systems.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"12597-12611"},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783384","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":"Solid-State NMR Validation of OPLS4: Structure of PC-Lipid Bilayers and Its Modulation by Dehydration.","authors":"Milla Kurki, Alexey M Nesterenko, Nicolai E Alsaker, Tiago M Ferreira, Sami Kyllönen, Antti Poso, Piia Bartos, Markus S Miettinen","doi":"10.1021/acs.jpcb.4c04719","DOIUrl":"10.1021/acs.jpcb.4c04719","url":null,"abstract":"<p><p>Atomistic molecular dynamics (MD) simulations are a much-used tool for investigating the structure and dynamics of biomembranes with atomic resolution. The validity of the representations obtained is determined by the accuracy and realism of the MD model (force field). Here, we evaluated the proprietary OPLS4 force field of Schrödinger, Inc. against atomic-resolution experimental data, and compared its performance to CHARMM36, one of the best-performing openly available force fields. As a benchmark, we used high-resolution nuclear magnetic resonance (NMR) order parameters for C-H bonds─directly and reliably calculable from MD simulations─measured in phosphatidylcholine (PC) lipid bilayers under varying hydration conditions. Comparisons were made with two dehydration data sets: for saturated (1,2-dimyristoylphosphatidylcholine, DMPC) lipid bilayers from the literature and for unsaturated (1-palmitoyl-2-oleoylphosphatidylcholine, POPC) lipid bilayers measured here. Our findings indicate that OPLS4 reproduces the structure and dehydration response of PC-lipid bilayers fairly well, even slightly outperforming CHARMM36. Both models' main inaccuracies appear in (1) the order parameter magnitudes in the glycerol backbone and unsaturated carbon segments and (2) the qualitatively differing structural response of the PC headgroup to dehydration compared to experiments. In summary, this work underscores the importance of independent validation for (proprietary) force fields and highlights the striking similarities and nuanced differences between OPLS4 and CHARMM36 in describing biomembranes.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"12483-12492"},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798800","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":"Dynamics of Nanoparticles in Solutions of Semiflexible Ring Polymers.","authors":"Shivraj B Kotkar, Ryan Poling-Skutvik, Michael P Howard, Arash Nikoubashman, Jacinta C Conrad, Jeremy C Palmer","doi":"10.1021/acs.jpcb.4c05674","DOIUrl":"10.1021/acs.jpcb.4c05674","url":null,"abstract":"<p><p>We use hybrid molecular dynamics-multiparticle collision dynamics (MD-MPCD) simulations to investigate the influence of chain stiffness on the transport of nanoparticles (NPs) through solutions of semiflexible ring polymers. The NPs exhibit subdiffusive dynamics on short time scales before transitioning to normal diffusion at longer times. The terminal NP diffusivity decreases with increasing ring stiffness, similar to the behavior observed in solutions of semiflexible linear chains. The NP subdiffusive exponent is found to be strongly correlated with that of the polymer center of mass (COM) for the range of chain stiffnesses examined, which is at odds with the pronounced decoupling of the NP and polymer COM motions previously observed upon increasing the stiffness of linear chains. Our analysis indicates that these marked differences in the intermediate dynamics are rooted in distinct structural changes that emerge with increasing bending stiffness: Stiffer ring polymers adopt increasingly circular conformations and stack into transient tubes. The void space created near the ring centers is occupied by NPs and other polymers, resulting in strong dynamic coupling on short time scales.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"12586-12596"},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783375","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}