Pub Date : 2024-07-02DOI: 10.1021/acs.jpcb.4c01906
Cristian M O Lépori, M Alejandra Luna, Cecilia Challier, Paola R Beassoni, N Mariano Correa, R Dario Falcone
Two ionic liquids (ILs) with amphiphilic properties composed of 1-butyl-3-methylimidazolium dioctylsulfosuccinate (bmim-AOT) and 1-hexyl-3-methylimidazolium dioctylsulfosuccinate (hmim-AOT) form unilamellar vesicles spontaneously simply by dissolving the IL-like surfactant in water. These novel vesicles were characterized using two different and highly sensitive fluorescent probes: 6-propionyl-2-(dimethylaminonaphthalene) (PRODAN) and trans-4-[4-(dimethylamino)-styryl]-1-methylpyridinium iodide (HC). These fluorescent probes provide information about the physicochemical properties of the bilayer, such as micropolarity, microviscosity, and electron-donor capacity. In addition, the biocompatibility of these vesicles with the blood medium was evaluated, and their toxicity was determined using Dictyostelium discoideum amoebas. First, using PRODAN and HC, it was found that the bilayer composition and the chemical structure of the ions at the interface produced differences between both amphiphiles, making the vesicles different. Thus, the bilayer of hmim-AOT vesicles is less polar, more rigid, and has a lower electron-donor capacity than those made by bmim-AOT. Finally, the results obtained from the hemolysis studies and the growth behavior of unicellular amoebas, particularly utilizing the D. discoideum assay, showed that both vesicular systems do not produce toxic effects up to a concentration of 0.02 mg/mL. This elegant assay, devoid of animal usage, highlights the potential of these newly organized systems for the delivery of drugs and bioactive molecules of different polarities.
由 1-丁基-3-甲基咪唑鎓二辛基磺基琥珀酸盐(bmim-AOT)和 1-己基-3-甲基咪唑鎓二辛基磺基琥珀酸盐(hmim-AOT)组成的两种具有两亲特性的离子液体(IL),只需将类似 IL 的表面活性剂溶解在水中,就能自发形成单酰胺囊泡。使用两种不同的高灵敏度荧光探针对这些新型囊泡进行了表征:6-丙酰基-2-(二甲氨基萘)(PRODAN)和反式-4-[4-(二甲基氨基)-苯乙烯基]-1-甲基吡啶鎓碘化物(HC)。这些荧光探针可提供双分子层的理化性质信息,如微泼度、微粘度和电子供体能力。此外,还评估了这些囊泡与血液培养基的生物相容性,并使用盘基变形虫测定了它们的毒性。首先,利用 PRODAN 和 HC 发现,这两种双亲化合物的双分子层组成和界面上离子的化学结构产生了差异,从而使囊泡有所不同。因此,与 bmim-AOT 相比,hmim-AOT 囊泡的双分子层极性更弱、刚性更大、电子供体能力更低。最后,从溶血研究和单细胞变形虫的生长行为(特别是利用 D. discoideum 试验)中获得的结果表明,这两种囊泡系统在 0.02 毫克/毫升的浓度下都不会产生毒性作用。这种无需使用动物的优雅检测方法,凸显了这些新组织系统在递送不同极性的药物和生物活性分子方面的潜力。
{"title":"Exploring the Properties of Unilamellar Vesicle Bilayers Formed by Ionic Liquid Surfactants for Future Applications in Nanomedicine.","authors":"Cristian M O Lépori, M Alejandra Luna, Cecilia Challier, Paola R Beassoni, N Mariano Correa, R Dario Falcone","doi":"10.1021/acs.jpcb.4c01906","DOIUrl":"https://doi.org/10.1021/acs.jpcb.4c01906","url":null,"abstract":"<p><p>Two ionic liquids (ILs) with amphiphilic properties composed of 1-butyl-3-methylimidazolium dioctylsulfosuccinate (bmim-AOT) and 1-hexyl-3-methylimidazolium dioctylsulfosuccinate (hmim-AOT) form unilamellar vesicles spontaneously simply by dissolving the IL-like surfactant in water. These novel vesicles were characterized using two different and highly sensitive fluorescent probes: 6-propionyl-2-(dimethylaminonaphthalene) (PRODAN) and <i>trans</i>-4-[4-(dimethylamino)-styryl]-1-methylpyridinium iodide (HC). These fluorescent probes provide information about the physicochemical properties of the bilayer, such as micropolarity, microviscosity, and electron-donor capacity. In addition, the biocompatibility of these vesicles with the blood medium was evaluated, and their toxicity was determined using <i>Dictyostelium discoideum</i> amoebas. First, using PRODAN and HC, it was found that the bilayer composition and the chemical structure of the ions at the interface produced differences between both amphiphiles, making the vesicles different. Thus, the bilayer of hmim-AOT vesicles is less polar, more rigid, and has a lower electron-donor capacity than those made by bmim-AOT. Finally, the results obtained from the hemolysis studies and the growth behavior of unicellular amoebas, particularly utilizing the <i>D. discoideum</i> assay, showed that both vesicular systems do not produce toxic effects up to a concentration of 0.02 mg/mL. This elegant assay, devoid of animal usage, highlights the potential of these newly organized systems for the delivery of drugs and bioactive molecules of different polarities.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490006","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}
Pub Date : 2024-07-02DOI: 10.1021/acs.jpcb.4c02359
Yanlin Li, Sangjun Yoo, Wei Bu, Honghu Zhang, Pulak Dutta
Specific ion effects in the interactions of monovalent anions with amine groups─one of the hydrophilic moieties found in proteins─were investigated using octadecylamine monolayers floating at air-aqueous solution interfaces. We find that at solution pH 5.7, larger monovalent anions induce a nonzero pressure starting at higher areas/molecules, i.e., a wider "liquid expanded" region in the monolayer isotherms. Using X-ray fluorescence at near total reflection (XFNTR), an element- and surface-specific technique, ion adsorption to the amines at pH 5.7 is confirmed to be ion-specific and to follow the conventional Hofmeister series. However, at pH 4, this ion specificity is no longer observed. We propose that at the higher pH, the amine headgroups are only partially protonated, and large polarizable ions such as iodine are better able to boost amine protonation. At the lower pH, on the other hand, the monolayer is fully protonated, and electrostatic interactions dominate over ion specificity. These results demonstrate that ion specificity can be modified by changing the experimental conditions.
{"title":"Modifying Specific Ion Effects: Studies of Monovalent Ion Interactions with Amines.","authors":"Yanlin Li, Sangjun Yoo, Wei Bu, Honghu Zhang, Pulak Dutta","doi":"10.1021/acs.jpcb.4c02359","DOIUrl":"https://doi.org/10.1021/acs.jpcb.4c02359","url":null,"abstract":"<p><p>Specific ion effects in the interactions of monovalent anions with amine groups─one of the hydrophilic moieties found in proteins─were investigated using octadecylamine monolayers floating at air-aqueous solution interfaces. We find that at solution pH 5.7, larger monovalent anions induce a nonzero pressure starting at higher areas/molecules, i.e., a wider \"liquid expanded\" region in the monolayer isotherms. Using X-ray fluorescence at near total reflection (XFNTR), an element- and surface-specific technique, ion adsorption to the amines at pH 5.7 is confirmed to be ion-specific and to follow the conventional Hofmeister series. However, at pH 4, this ion specificity is no longer observed. We propose that at the higher pH, the amine headgroups are only partially protonated, and large polarizable ions such as iodine are better able to boost amine protonation. At the lower pH, on the other hand, the monolayer is fully protonated, and electrostatic interactions dominate over ion specificity. These results demonstrate that ion specificity can be modified by changing the experimental conditions.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490007","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}
Pub Date : 2024-07-02DOI: 10.1021/acs.jpcb.4c01171
Ning Wu, Yingguang Liu, Zhibo Xing, Shuo Wang, Cheng Zhang
One-dimensional van der Waals (vdWs) heterostructures are celebrated for their exceptional thermal management capabilities, garnering significant research interest. Consequently, our research focused on the one-dimensional vdWs heterojunction comprising carbon nanotube half-wrapped in boron nitride nanotube (BNCNT), specifically their thermal rectification (TR) properties. We employed non-equilibrium molecular dynamics to explore the TR mechanism and assess the impacts of temperature, strain, and coupling strength on heat flux and TR ratio. Our findings reveal that the backward heat flux demonstrates greater atomic vibration instability, as indicated by mean square displacement (MSD), compared to forward heat flux. This instability leads to a higher concentration of localized phonons, thereby diminishing the backward heat flux and enhancing TR. Additionally, we utilized MSD to shed light on the negative differential thermal resistance phenomenon and the influence of stress on forward and backward heat fluxes. Remarkably, TR ratios reached 344% at 3% strain and 400% at -1% strain. Calculations of phonon density of states revealed a competitive mechanism between in-plane and out-of-plane phonons coupling in the inner carbon nanotube and an overlap degree of out-of-plane phonon spectra between the inner carbon nanotube and outer boron nitride nanotube. This accounts for the differing trends in forward and backward heat fluxes as coupling strength χ increases, with TR ratios exceeding 1000% at χ = 7.5. This study provides vital insights for advancing one-dimensional vdWs thermal rectifiers.
{"title":"One-Dimensional van der Waals Heterojunction Comprising Carbon Nanotube Half-Wrapped in Boron Nitride Nanotube: Deep Investigation of Thermal Rectification.","authors":"Ning Wu, Yingguang Liu, Zhibo Xing, Shuo Wang, Cheng Zhang","doi":"10.1021/acs.jpcb.4c01171","DOIUrl":"https://doi.org/10.1021/acs.jpcb.4c01171","url":null,"abstract":"<p><p>One-dimensional van der Waals (vdWs) heterostructures are celebrated for their exceptional thermal management capabilities, garnering significant research interest. Consequently, our research focused on the one-dimensional vdWs heterojunction comprising carbon nanotube half-wrapped in boron nitride nanotube (BNCNT), specifically their thermal rectification (TR) properties. We employed non-equilibrium molecular dynamics to explore the TR mechanism and assess the impacts of temperature, strain, and coupling strength on heat flux and TR ratio. Our findings reveal that the backward heat flux demonstrates greater atomic vibration instability, as indicated by mean square displacement (MSD), compared to forward heat flux. This instability leads to a higher concentration of localized phonons, thereby diminishing the backward heat flux and enhancing TR. Additionally, we utilized MSD to shed light on the negative differential thermal resistance phenomenon and the influence of stress on forward and backward heat fluxes. Remarkably, TR ratios reached 344% at 3% strain and 400% at -1% strain. Calculations of phonon density of states revealed a competitive mechanism between in-plane and out-of-plane phonons coupling in the inner carbon nanotube and an overlap degree of out-of-plane phonon spectra between the inner carbon nanotube and outer boron nitride nanotube. This accounts for the differing trends in forward and backward heat fluxes as coupling strength χ increases, with TR ratios exceeding 1000% at χ = 7.5. This study provides vital insights for advancing one-dimensional vdWs thermal rectifiers.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490009","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}
A combined experimental and simulation study of dielectric relaxation (DR) of a deep eutectic solvent (DES) composed of betaine, urea, and water with the composition [Betaine:Urea:Water = 11.7:12:1 (weight ratio) and 9:18:5 (molar ratio)] was performed to explore and understand the interaction and dynamics of this system. Temperature-dependent (303 ≤ T/K ≤ 343) measurements were performed over 9 decades of frequency, combining three different measurement setups. Measured DR, comprising four distinct steps with relaxation times spreading over a few picoseconds to several nanoseconds, was found to agree well with simulations. The simulated total DR spectra, upon dissection into three self (intraspecies) and three cross (interspecies) interaction contributions, revealed that the betaine-betaine self-term dominated (∼65%) the relaxation, while the urea-urea and water-water interactions contributed only ∼7% and ∼1%, respectively. The cross-terms (betaine-urea, betaine-water, and urea-water) together accounted for <30% of the total DR. The slowest DR component with a time constant of ∼1-10 ns derived dominant contribution from betaine-betaine interactions, where betaine-water and urea-water interactions also contributed. The subnanosecond (0.1-0.6 ns) time scale originated from all interactions except betaine-water interaction. An extensive interaction of water with betaine and urea severely reduced the average number of water-water H-bonds (∼0.7) and heavily decreased the static dielectric constant of water in this DES (εs ∼ 2). Furthermore, simulated first rank collective single particle reorientational relaxations (C1(t)) and the structural H-bond fluctuation dynamics (CHB (t)) exhibited multiexponential kinetics with time scales that corresponded well with those found both in the simulated and measured DR.
为了探索和理解该系统的相互作用和动力学,我们对甜菜碱、尿素和水组成的深共晶溶剂(DES)的介电弛豫(DR)进行了实验和模拟相结合的研究,其组成为[甜菜碱:尿素:水 = 11.7:12:1(重量比)和 9:18:5(摩尔比)]。结合三种不同的测量设置,在 9 个十年频率范围内进行了随温度变化(303 ≤ T/K ≤ 343)的测量。测量到的 DR 包括四个不同的步骤,弛豫时间从几皮秒到几纳秒不等,与模拟结果十分吻合。将模拟的总弛豫光谱分解为三个自身(种内)和三个交叉(种间)相互作用贡献后发现,甜菜碱-甜菜碱自身项主导了弛豫(∼65%),而尿素-尿素和水-水相互作用分别只贡献了∼7%和∼1%。交叉作用(甜菜碱-尿素、甜菜碱-水和尿素-水)共占 s ∼ 2)。此外,模拟的第一级集体单粒子重取向弛豫(C1(t))和结构 H 键波动动力学(CHB(t))表现出多指数动力学,其时间尺度与模拟和测量的 DR 中发现的时间尺度十分吻合。
{"title":"Temperature-Dependent Dielectric Relaxation Measurements of (Betaine + Urea + Water) Deep Eutectic Solvent in Hz-GHz Frequency Window: Microscopic Insights into Constituent Contributions and Relaxation Mechanisms.","authors":"Jayanta Mondal, Dhrubajyoti Maji, Sudipta Mitra, Ranjit Biswas","doi":"10.1021/acs.jpcb.4c02784","DOIUrl":"https://doi.org/10.1021/acs.jpcb.4c02784","url":null,"abstract":"<p><p>A combined experimental and simulation study of dielectric relaxation (DR) of a deep eutectic solvent (DES) composed of betaine, urea, and water with the composition [Betaine:Urea:Water = 11.7:12:1 (weight ratio) and 9:18:5 (molar ratio)] was performed to explore and understand the interaction and dynamics of this system. Temperature-dependent (303 ≤ <i>T</i>/<i>K</i> ≤ 343) measurements were performed over 9 decades of frequency, combining three different measurement setups. Measured DR, comprising four distinct steps with relaxation times spreading over a few picoseconds to several nanoseconds, was found to agree well with simulations. The simulated total DR spectra, upon dissection into three self (intraspecies) and three cross (interspecies) interaction contributions, revealed that the betaine-betaine self-term dominated (∼65%) the relaxation, while the urea-urea and water-water interactions contributed only ∼7% and ∼1%, respectively. The cross-terms (betaine-urea, betaine-water, and urea-water) together accounted for <30% of the total DR. The slowest DR component with a time constant of ∼1-10 ns derived dominant contribution from betaine-betaine interactions, where betaine-water and urea-water interactions also contributed. The subnanosecond (0.1-0.6 ns) time scale originated from all interactions except betaine-water interaction. An extensive interaction of water with betaine and urea severely reduced the average number of water-water H-bonds (∼0.7) and heavily decreased the static dielectric constant of water in this DES (ε<sub>s</sub> ∼ 2). Furthermore, simulated first rank collective single particle reorientational relaxations (<i>C</i><sub>1</sub>(<i>t</i>)) and the structural H-bond fluctuation dynamics (<i>C</i><sub>HB</sub> (<i>t</i>)) exhibited multiexponential kinetics with time scales that corresponded well with those found both in the simulated and measured DR.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464336","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}
Pub Date : 2024-07-01DOI: 10.1021/acs.jpcb.4c02823
Zixin Hu, Tiedong Sun, Wenwen Chen, Lars Nordenskiöld, Lanyuan Lu
Coarse-grained models designed for intrinsically disordered proteins and regions (IDP/Rs) usually omit some bonded potentials (e.g., angular and dihedral potentials) as a conventional strategy to enhance backbone flexibility. However, a notable drawback of this approach is the generation of inaccurate backbone conformations. Here, we addressed this problem by introducing residue-specific angular, refined dihedral, and correction map (CMAP) potentials, derived based on the statistics from a customized coil database. These bonded potentials were integrated into the existing Mpipi model, resulting in a new model, denoted as the "Mpipi+" model. Results show that the Mpipi+ model can improve backbone conformations. More importantly, it can markedly improve the secondary structure propensity (SSP) based on the experimental chemical shift and, consequently, succeed in capturing transient secondary structures. Moreover, the Mpipi+ model preserves the liquid-liquid phase separation (LLPS) propensities of IDPs.
{"title":"Refined Bonded Terms in Coarse-Grained Models for Intrinsically Disordered Proteins Improve Backbone Conformations.","authors":"Zixin Hu, Tiedong Sun, Wenwen Chen, Lars Nordenskiöld, Lanyuan Lu","doi":"10.1021/acs.jpcb.4c02823","DOIUrl":"https://doi.org/10.1021/acs.jpcb.4c02823","url":null,"abstract":"<p><p>Coarse-grained models designed for intrinsically disordered proteins and regions (IDP/Rs) usually omit some bonded potentials (e.g., angular and dihedral potentials) as a conventional strategy to enhance backbone flexibility. However, a notable drawback of this approach is the generation of inaccurate backbone conformations. Here, we addressed this problem by introducing residue-specific angular, refined dihedral, and correction map (CMAP) potentials, derived based on the statistics from a customized coil database. These bonded potentials were integrated into the existing Mpipi model, resulting in a new model, denoted as the \"Mpipi+\" model. Results show that the Mpipi+ model can improve backbone conformations. More importantly, it can markedly improve the secondary structure propensity (SSP) based on the experimental chemical shift and, consequently, succeed in capturing transient secondary structures. Moreover, the Mpipi+ model preserves the liquid-liquid phase separation (LLPS) propensities of IDPs.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141475465","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}
Proton (H+) motive force (PMF) serves as the energy source for the flagellar motor rotation, crucial for microbial motility. Here, to control PMF using light, we introduced light-driven inward and outward proton pump rhodopsins, RmXeR and AR3, into Escherichia coli. The motility of E. coli cells expressing RmXeR and AR3 significantly decreased and increased upon illumination, respectively. Tethered cell experiments revealed that, upon illumination, the torque of the flagellar motor decreased to nearly zero (28 pN nm) with RmXeR, while it increased to 1170 pN nm with AR3. These alterations in PMF correspond to +146 mV (RmXeR) and -140 mV (AR3), respectively. Thus, bidirectional optical control of PMF in E. coli was successfully achieved by using proton pump rhodopsins. This system holds a potential for enhancing our understanding of the roles of PMF in various biological functions.
{"title":"Bidirectional Optical Control of Proton Motive Force in <i>Escherichia coli</i> Using Microbial Rhodopsins.","authors":"Kotaro Nakanishi, Keiichi Kojima, Yoshiyuki Sowa, Yuki Sudo","doi":"10.1021/acs.jpcb.4c03027","DOIUrl":"https://doi.org/10.1021/acs.jpcb.4c03027","url":null,"abstract":"<p><p>Proton (H<sup>+</sup>) motive force (PMF) serves as the energy source for the flagellar motor rotation, crucial for microbial motility. Here, to control PMF using light, we introduced light-driven inward and outward proton pump rhodopsins, <i>Rm</i>XeR and AR3, into <i>Escherichia coli</i>. The motility of <i>E. coli</i> cells expressing <i>Rm</i>XeR and AR3 significantly decreased and increased upon illumination, respectively. Tethered cell experiments revealed that, upon illumination, the torque of the flagellar motor decreased to nearly zero (28 pN nm) with <i>Rm</i>XeR, while it increased to 1170 pN nm with AR3. These alterations in PMF correspond to +146 mV (<i>Rm</i>XeR) and -140 mV (AR3), respectively. Thus, bidirectional optical control of PMF in <i>E. coli</i> was successfully achieved by using proton pump rhodopsins. This system holds a potential for enhancing our understanding of the roles of PMF in various biological functions.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464414","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}
Pub Date : 2024-07-01DOI: 10.1021/acs.jpcb.4c02699
Maria Carolina P Lima, Braxten D Hornsby, Carol S Lim, Thomas E Cheatham
The chimeric oncoprotein Bcr-Abl is the causative agent of virtually all chronic myeloid leukemias and a subset of acute lymphoblastic leukemias. As a result of the so-called Philadelphia chromosome translocation t(9;22), Bcr-Abl manifests as a constitutively active tyrosine kinase, which promotes leukemogenesis by activation of cell cycle signaling pathways. Constitutive and oncogenic activation is mediated by an N-terminal coiled-coil oligomerization domain in Bcr (Bcr-CC), presenting a therapeutic target for inhibition of Bcr-Abl activity toward the treatment of Bcr-Abl+ leukemias. Previously, we demonstrated that a rationally designed Bcr-CC mutant, CCmut3, exerts a dominant negative effect upon Bcr-Abl activity by preferential oligomerization with Bcr-CC. Moreover, we have shown that conjugation to a leukemia-specific cell-penetrating peptide (CPP-CCmut3) improves intracellular delivery and activity. However, our full-length CPP-CCmut3 construct (81 aa) is encumbered by an intrinsically high degree of conformational variability and susceptibility to proteolytic degradation relative to traditional small-molecule therapeutics. Here, we iterate a new generation of CCmut3 inhibitors against Bcr-CC-mediated Bcr-Abl assembly designed to address these constraints through incorporation of all-hydrocarbon staples spanning i and i + 7 positions in α-helix 2 (CPP-CCmut3-st). We utilize computational modeling and biomolecular simulation to evaluate single- and double-stapled CCmut3 candidates in silico for dynamics and binding energetics. We further model a truncated system characterized by the deletion of α-helix 1 and the flexible loop linker, which are known to impart high conformational variability. To study the impact of the N-terminal cyclic CPP toward model stability and inhibitor activity, we also model the full-length and truncated systems devoid of the CPP, with a cyclized CPP, and with an open-configuration CPP, for a total of six systems that comprise our library. From this library, we present lead-stapled peptide candidates to be synthesized and evaluated experimentally as our next iteration of inhibitors against Bcr-Abl.
{"title":"Molecular Modeling of Single- and Double-Hydrocarbon-Stapled Coiled-Coil Inhibitors against Bcr-Abl: Toward a Treatment Strategy for CML.","authors":"Maria Carolina P Lima, Braxten D Hornsby, Carol S Lim, Thomas E Cheatham","doi":"10.1021/acs.jpcb.4c02699","DOIUrl":"https://doi.org/10.1021/acs.jpcb.4c02699","url":null,"abstract":"<p><p>The chimeric oncoprotein Bcr-Abl is the causative agent of virtually all chronic myeloid leukemias and a subset of acute lymphoblastic leukemias. As a result of the so-called Philadelphia chromosome translocation t(9;22), Bcr-Abl manifests as a constitutively active tyrosine kinase, which promotes leukemogenesis by activation of cell cycle signaling pathways. Constitutive and oncogenic activation is mediated by an N-terminal coiled-coil oligomerization domain in Bcr (Bcr-CC), presenting a therapeutic target for inhibition of Bcr-Abl activity toward the treatment of Bcr-Abl<sup>+</sup> leukemias. Previously, we demonstrated that a rationally designed Bcr-CC mutant, CCmut3, exerts a dominant negative effect upon Bcr-Abl activity by preferential oligomerization with Bcr-CC. Moreover, we have shown that conjugation to a leukemia-specific cell-penetrating peptide (CPP-CCmut3) improves intracellular delivery and activity. However, our full-length CPP-CCmut3 construct (81 aa) is encumbered by an intrinsically high degree of conformational variability and susceptibility to proteolytic degradation relative to traditional small-molecule therapeutics. Here, we iterate a new generation of CCmut3 inhibitors against Bcr-CC-mediated Bcr-Abl assembly designed to address these constraints through incorporation of all-hydrocarbon staples spanning <i>i</i> and <i>i</i> + 7 positions in α-helix 2 (CPP-CCmut3-st). We utilize computational modeling and biomolecular simulation to evaluate single- and double-stapled CCmut3 candidates <i>in silico</i> for dynamics and binding energetics. We further model a truncated system characterized by the deletion of α-helix 1 and the flexible loop linker, which are known to impart high conformational variability. To study the impact of the N-terminal cyclic CPP toward model stability and inhibitor activity, we also model the full-length and truncated systems devoid of the CPP, with a cyclized CPP, and with an open-configuration CPP, for a total of six systems that comprise our library. From this library, we present lead-stapled peptide candidates to be synthesized and evaluated experimentally as our next iteration of inhibitors against Bcr-Abl.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141475464","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}
Pub Date : 2024-07-01DOI: 10.1021/acs.jpcb.4c01894
Ziyang Liu, Sheng Gui, Benzhuo Lu, Linbo Zhang
So far, the existing Poisson-Boltzmann (PB) solvers that accurately take into account the interface jump conditions need a pregenerated body-fitted mesh (molecular surface mesh). However, qualified biomolecular surface meshing and its implementation into numerical methods remains a challenging and laborious issue, which practically hinders the progress of further developments and applications of a bunch of numerical methods in this field. In addition, even with a molecular surface mesh, it is only a low-order approximation of the original curved surface. In this article, an interface-penalty finite element method (IPFEM), which is a typical unfitted finite element method, is proposed to solve the Poisson-Boltzmann equation (PBE) without requiring the user to generate a molecular surface mesh. The Gaussian molecular surface is used to represent the molecular surface and can be automatically resolved with a high-order approximation within our method. Theoretical convergence rates of the IPFEM for the linear PB equation have been provided and are well validated on a benchmark problem with an analytical solution (we also noticed from numerical examples that the IPFEM has similar convergence rates for the nonlinear PBE). Numerical results on a set of different-sized biomolecules demonstrate that the IPFEM is numerically stable and accurate in the calculation of biomolecular electrostatic solvation energy.
{"title":"An Unfitted Finite Element Poisson-Boltzmann Solver with Automatic Resolving of Curved Molecular Surface.","authors":"Ziyang Liu, Sheng Gui, Benzhuo Lu, Linbo Zhang","doi":"10.1021/acs.jpcb.4c01894","DOIUrl":"https://doi.org/10.1021/acs.jpcb.4c01894","url":null,"abstract":"<p><p>So far, the existing Poisson-Boltzmann (PB) solvers that accurately take into account the interface jump conditions need a pregenerated body-fitted mesh (molecular surface mesh). However, qualified biomolecular surface meshing and its implementation into numerical methods remains a challenging and laborious issue, which practically hinders the progress of further developments and applications of a bunch of numerical methods in this field. In addition, even with a molecular surface mesh, it is only a low-order approximation of the original curved surface. In this article, an interface-penalty finite element method (IPFEM), which is a typical unfitted finite element method, is proposed to solve the Poisson-Boltzmann equation (PBE) without requiring the user to generate a molecular surface mesh. The Gaussian molecular surface is used to represent the molecular surface and can be automatically resolved with a high-order approximation within our method. Theoretical convergence rates of the IPFEM for the linear PB equation have been provided and are well validated on a benchmark problem with an analytical solution (we also noticed from numerical examples that the IPFEM has similar convergence rates for the nonlinear PBE). Numerical results on a set of different-sized biomolecules demonstrate that the IPFEM is numerically stable and accurate in the calculation of biomolecular electrostatic solvation energy.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141475462","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}
Pub Date : 2024-07-01DOI: 10.1021/acs.jpcb.3c08422
Shiwei Su, Tsukuru Masuda, Madoka Takai
Polymer informatics has attracted increasing attention as a specialized branch of material informatics. Hydrophilicity/hydrophobicity is one of the most important properties of interfaces involved in antifouling, self-cleaning, antifogging, oil/water separation, protein adsorption, and bioseparation. Establishing a quantitative structure-property relationship for the hydrophilicity/hydrophobicity of polymeric interfaces could significantly benefit from machine learning modeling. In this study, we aimed to construct machine learning models that could predict the static water contact angle (CA) as an indicator of hydrophilicity/hydrophobicity based on a data set of polymer brushes. The features of the polymer brush surfaces were numerically described using their grafted structures (thickness) and molecular descriptors derived from their chemical structures. We achieved accurate prediction and understanding of important parameters by employing appropriate molecular descriptors considering the Pearson correlation and machine learning models trained with nested cross-validation. The model interpretation by Shapley additive extension analysis indicated that the amount of partial polar/nonpolar structure in the molecule as well as the averaged hydrophobicity represented by MolLogP plays an important role in determining the CA. Moreover, the model can predict the CAs of polymer brushes composed of chemical structures that are not present in existing databases. The CA values of the hypothetical polymer brushes are predicted.
聚合物信息学作为材料信息学的一个专业分支,已引起越来越多的关注。亲水性/疏水性是涉及防污、自洁、防雾、油/水分离、蛋白质吸附和生物分离的界面的最重要特性之一。为聚合物界面的亲水性/疏水性建立定量的结构-性能关系,将极大地受益于机器学习建模。在本研究中,我们旨在根据聚合物刷数据集构建机器学习模型,以预测静态水接触角(CA),作为亲水性/疏水性的指标。聚合物刷表面的特征是利用其接枝结构(厚度)和从其化学结构中提取的分子描述符进行数值描述的。通过使用适当的分子描述符(考虑到皮尔逊相关性)和经过嵌套交叉验证训练的机器学习模型,我们实现了对重要参数的准确预测和理解。通过 Shapley 加性延伸分析对模型的解释表明,分子中部分极性/非极性结构的数量以及 MolLogP 所代表的平均疏水性在决定 CA 方面起着重要作用。此外,该模型还能预测由现有数据库中不存在的化学结构组成的聚合物刷的 CA 值。该模型预测了假定聚合物刷的 CA 值。
{"title":"Explainable Prediction of Hydrophilic/Hydrophobic Property of Polymer Brush Surfaces by Chemical Modeling and Machine Learning.","authors":"Shiwei Su, Tsukuru Masuda, Madoka Takai","doi":"10.1021/acs.jpcb.3c08422","DOIUrl":"https://doi.org/10.1021/acs.jpcb.3c08422","url":null,"abstract":"<p><p>Polymer informatics has attracted increasing attention as a specialized branch of material informatics. Hydrophilicity/hydrophobicity is one of the most important properties of interfaces involved in antifouling, self-cleaning, antifogging, oil/water separation, protein adsorption, and bioseparation. Establishing a quantitative structure-property relationship for the hydrophilicity/hydrophobicity of polymeric interfaces could significantly benefit from machine learning modeling. In this study, we aimed to construct machine learning models that could predict the static water contact angle (CA) as an indicator of hydrophilicity/hydrophobicity based on a data set of polymer brushes. The features of the polymer brush surfaces were numerically described using their grafted structures (thickness) and molecular descriptors derived from their chemical structures. We achieved accurate prediction and understanding of important parameters by employing appropriate molecular descriptors considering the Pearson correlation and machine learning models trained with nested cross-validation. The model interpretation by Shapley additive extension analysis indicated that the amount of partial polar/nonpolar structure in the molecule as well as the averaged hydrophobicity represented by MolLogP plays an important role in determining the CA. Moreover, the model can predict the CAs of polymer brushes composed of chemical structures that are not present in existing databases. The CA values of the hypothetical polymer brushes are predicted.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141475463","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}
Pub Date : 2024-06-29DOI: 10.1021/acs.jpcb.4c02555
Wenbo Dong, Jan Blasius, Zhijie Fan, Luke Wylie
We present maximally localized Wannier functions and Voronoi tessellation to obtain dipole moment distributions for vibrational spectra in several important ionic liquids calculated by using ab initio molecular dynamics simulations. IR and Raman spectra of various imidazolium-based ionic liquids (ILs) paired with six amino acid anions are shown herein. For IR spectra, two approaches (Wannier and Voronoi) are in agreement with respect to the relative intensities and the overall shapes for the main peaks. Under Raman spectra, the polarizability of the covalent bonds is shown to affect the strength of the Raman scattering signal. The advantage of the Voronoi tessellation method, being that it does not have strong spikes in its time development, is demonstrated by the comparison of two theoretical methods (Wannier and Voronoi) with experimental data. We analyze the errors between theoretical and experimental spectroscopic data, with the Voronoi method shown to accurately reproduce experimental values. In addition, theoretical spectroscopy shows the ability to accurately separate components of a mixture. The combination of theoretical and experimental methods is utilized to understand the spectroscopic properties of amino acid-based imidazolium ILs.
我们提出了最大局部万尼尔函数和沃罗诺网格,以获得利用 ab initio 分子动力学模拟计算的几种重要离子液体振动光谱的偶极矩分布。本文展示了与六种氨基酸阴离子配对的各种咪唑基离子液体(ILs)的红外光谱和拉曼光谱。对于红外光谱,两种方法(Wannier 和 Voronoi)在主峰的相对强度和整体形状方面是一致的。在拉曼光谱中,共价键的极化性会影响拉曼散射信号的强度。通过将两种理论方法(Wannier 和 Voronoi)与实验数据进行比较,证明了 Voronoi 细分法的优势,即在时间发展过程中不会出现强烈的峰值。我们分析了理论光谱数据与实验光谱数据之间的误差,结果表明 Voronoi 方法准确地再现了实验值。此外,理论光谱学还显示了准确分离混合物成分的能力。理论和实验方法的结合被用来理解氨基酸基咪唑鎓 IL 的光谱特性。
{"title":"Vibrational Spectra Simulations in Amino Acid-Based Imidazolium Ionic Liquids.","authors":"Wenbo Dong, Jan Blasius, Zhijie Fan, Luke Wylie","doi":"10.1021/acs.jpcb.4c02555","DOIUrl":"https://doi.org/10.1021/acs.jpcb.4c02555","url":null,"abstract":"<p><p>We present maximally localized Wannier functions and Voronoi tessellation to obtain dipole moment distributions for vibrational spectra in several important ionic liquids calculated by using ab initio molecular dynamics simulations. IR and Raman spectra of various imidazolium-based ionic liquids (ILs) paired with six amino acid anions are shown herein. For IR spectra, two approaches (Wannier and Voronoi) are in agreement with respect to the relative intensities and the overall shapes for the main peaks. Under Raman spectra, the polarizability of the covalent bonds is shown to affect the strength of the Raman scattering signal. The advantage of the Voronoi tessellation method, being that it does not have strong spikes in its time development, is demonstrated by the comparison of two theoretical methods (Wannier and Voronoi) with experimental data. We analyze the errors between theoretical and experimental spectroscopic data, with the Voronoi method shown to accurately reproduce experimental values. In addition, theoretical spectroscopy shows the ability to accurately separate components of a mixture. The combination of theoretical and experimental methods is utilized to understand the spectroscopic properties of amino acid-based imidazolium ILs.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464338","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}