The Journal of Physical Chemistry B最新文献

{"title":"Using Machine Learning to Analyze Molecular Dynamics Simulations of Biomolecules.","authors":"Alfie-Louise R Brownless, Elisa Rheaume, Katie M Kuo, Shina C L Kamerlin, James C Gumbart","doi":"10.1021/acs.jpcb.4c08824","DOIUrl":"https://doi.org/10.1021/acs.jpcb.4c08824","url":null,"abstract":"<p><p>Machine learning (ML) techniques have become powerful tools in both industrial and academic settings. Their ability to facilitate analysis of complex data and generation of predictive insights is transforming how scientific problems are approached across a wide range of disciplines. In this tutorial, we present a cursory introduction to three widely used ML techniques─logistic regression, random forest, and multilayer perceptron─applied toward analyzing molecular dynamics (MD) trajectory data. We employ our chosen ML models to the study of the SARS-CoV-2 spike protein receptor binding domain interacting with the receptor ACE2. We develop a pipeline for processing MD simulation trajectory data and identifying residues that significantly impact the stability of the complex.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148682","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 Epidermal Growth Factor Receptor under Piconewton Mechanical Compressive Force Manipulations.","authors":"Dedunu S Senarathne, Lalita Shahu, H Peter Lu","doi":"10.1021/acs.jpcb.5c00800","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c00800","url":null,"abstract":"<p><p>Studying the relationship among protein structure, dynamics, and function under external compressive forces offers valuable insights. While extensive research has focused on manipulating protein dynamics and ligand-receptor interactions under pulling forces, the exploration of protein conformational changes under compressive forces has been limited. In this study, we investigate the response of unliganded epidermal growth factor receptor (EGFR) monomers, liganded EGF-EGFR monomers, and dimers when exposed to external compressive forces using a home-modified AFM setup with an ultrasoft AFM tip. We observed that both ligand-bound and unbound EGFR proteins can undergo spontaneous tertiary structural rupture under piconewton-level compressive forces, a previously hidden protein behavior that may play a significant role in protein cell signaling. The magnitudes of the threshold compressive forces obtained in our study lie in the range of tens and hundreds of piconewtons (pN), which is accessible within a live biological system. Moreover, we developed a kinetic model to exhibit that only a fraction of the uniaxial compressive force exerted by the AFM tip affects the internal tension that causes a pseudopulling force within the protein before it undergoes the tertiary structural rupture. This calculated fraction ranged from 0.45 to 0.65, depending on the protein type and the approach velocity of the AFM tip. Additionally, we employed molecular dynamics (MD) simulations, particularly Steered MD (SMD) simulations along with Umbrella Sampling (US), to investigate the dynamics of unliganded and liganded EGFR in the presence of external compressive forces. These MD simulation results offer valuable insights into the flexibilities and unfolding behaviors of both liganded and unliganded EGFR proteins when subjected to external compressive forces.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148679","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":"Mechanistic Insights into Choline Degradation Catalyzed by the Choline Trimethylamine-Lyase CutC.","authors":"Yi-Qian Yang, Wen-Hao Deng, Rong-Zhen Liao","doi":"10.1021/acs.jpcb.5c01496","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c01496","url":null,"abstract":"<p><p>Choline trimethylamine-lyase (CutC) is a prominent glycyl radical enzyme that catalyzes the degradation of choline into nitrogenous metabolites trimethylamine (TMA) and acetaldehyde. Choline and TMA are crucial nitrogen-containing compounds and play essential roles in various biological pathways, including neurotransmission and global metabolic functions. Although many experimental studies have been dedicated to elucidating the function of CutC, its exact catalytic mechanism remains elusive. Herein, we employed molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) methodologies to investigate the reaction mechanism of CutC in detail. Our calculation results reveal that the enzymatic reaction is initiated by a two-step hydrogen atom transfer (HAT) mechanism, a typical process mediated by a cysteine radical in glycyl radical enzymes (GREs). Significantly, in our suggested reaction mechanism, unlike the previously proposed 1,2-elimination pathway, a more favorable stepwise 1,2-migration of the TMA group occurs after the formation of a substrate radical. This migration of the TMA group leads to the formation of a hemiaminal intermediate, which is likely to be eliminated outside of CutC. Furthermore, our mechanistic investigations indicate that the residue Glu440, adjacent to the choline substrate, plays a pivotal role in helping substrate binding through a hydrogen bond rather than serving as a general base for proton abstraction. These findings provide deeper insights into the catalytic strategy that CutC employs for C-N bond cleavage in choline metabolism and broaden the mechanistic repertoire documented for glycyl radical enzymes in mediating elimination reactions.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148678","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":"Structural Transformations within the Solvate Ionic Liquid [Li(Triglyme)][NTf₂]: Implications for Self-Diffusion, Viscosity, and Ionic Conductivity.","authors":"Jule Kristin Philipp, Lennart Kruse, Dietmar Paschek, Ralf Ludwig","doi":"10.1021/acs.jpcb.5c01772","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c01772","url":null,"abstract":"<p><p>Solvate ionic liquids (SILs) are a promising new class of electrolytes for lithium-ion batteries. Prominent SIL candidates are equimolar mixtures of lithium salts with weakly interacting anions and glyme. In particular, the equimolar mixture of lithium bis(trifluoromethanesulfonyl)imide ([Li][NTf₂]) and triglyme (G3) is of great interest. It has been suggested that this mixture exhibits a behavior similar to ionic liquids due to the formation of stable 1:1 complexes of [Li]⁺ with G3 molecules. We use up to multimicrosecond molecular dynamics (MD) simulations to better understand the structure and dynamics of the mixtures for varying mixing ratios and temperatures and to characterize the typical coordination patterns of the [Li]⁺ complexes. We find that at low [Li][NTf₂] content, each [Li]⁺ cation is, on average, coordinated by two G3 molecules. For nearly equimolar mixtures, the complex changes to a one-fold G3-coordinated cation plus one additional anion. For higher than equimolar salt concentrations, cations are increasingly surrounded by their counterions, forming lithium bridges between adjacent anions. We observe that the structure primarily depends on the mixture composition, while it is remarkably temperature-insensitive. The latter suggests that cluster equilibria in the SIL are subject to only small entropy differences, retaining the SIL-like structural features up to more than 200 °C. We demonstrate that the structural changes have a major impact on the transport properties of the system. For the investigated temperatures, the self-diffusion coefficients of all components decrease by several orders of magnitude with increasing [Li][NTf₂] content, while the viscosity strongly increases. For mole fractions between 0.4 and 0.5, both [Li]⁺ and G3 move concertedly and exhibit similar self-diffusion coefficients, indicating the formation of stable 1:1 complexes. We conclude that these mixtures can be categorized as highly temperature-stable SILs with possible implications for battery technology.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148681","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":"Transferability of MACE Graph Neural Network for Range Corrected Δ-Machine Learning Potential QM/MM Applications.","authors":"Timothy J Giese, Jinzhe Zeng, Darrin M York","doi":"10.1021/acs.jpcb.5c02006","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c02006","url":null,"abstract":"<p><p>We previously introduced a \"range corrected\" Δ-machine learning potential (ΔMLP) that used deep neural networks to improve the accuracy of combined quantum mechanical/molecular mechanical (QM/MM) simulations by correcting both the internal QM and QM/MM interaction energies and forces [J. Chem. Theory Comput. 2021, 17, 6993-7009]. The present work extends this approach to include graph neural networks. Specifically, the approach is applied to the MACE message passing neural network architecture, and a series of AM1/d + MACE models are trained to reproduce PBE0/6-31G* QM/MM energies and forces of model phosphoryl transesterification reactions. Several models are designed to test the transferability of AM1/d + MACE by varying the amount of training data and calculating free energy surfaces of reactions that were not included in the parameter refinement. The transferability is compared to AM1/d + DP models that use the DeepPot-SE (DP) deep neural network architecture. The AM1/d + MACE models are found to reproduce the target free energy surfaces even in instances where the AM1/d + DP models exhibit inaccuracies. We train \"end-state\" models that include data only from the reactant and product states of the 6 reactions. Unlike the uncorrected AM1/d profiles, the AM1/d + MACE method correctly reproduces a stable pentacoordinated phosphorus intermediate even though the training did not include structures with a similar bonding pattern. Furthermore, the message passing mechanism hyperparameters defining the MACE network are varied to explore their effect on the model's accuracy and performance. The AM1/d + MACE simulations are 28% slower than AM1/d QM/MM when the ΔMLP correction is performed on a graphics processing unit. Our results suggest that the MACE architecture may lead to ΔMLP models with improved transferability.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140963","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":"Single-Lipid Diffusion Behaviors in Cell Membranes Modulated by Cholesterol-Based Heterogeneity.","authors":"Xiao Xu, Cheng Xu, Wanting Zhang, Zhiheng Liu, Yushuang Wei, Kai Yang, Bing Yuan","doi":"10.1021/acs.jpcb.5c01625","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c01625","url":null,"abstract":"<p><p>Over a century after the proposal of Fluid Mosaic Model, the relationship between functionally related multiple-scale spatial heterogeneity of the cell membrane and mobility of component molecules, both inherent features of cell membrane, remains elusive. Single-lipid tracking enables the analysis of structural heterogeneity at different spatial scales within the cell membrane from a lipid diffusion perspective. Herein, specifically designed cholesterol (Chol)-based membrane systems were utilized to investigate the distinct impacts of molecular-level interactions between diverse membrane components and micrometer-scale spatial confinement on lipid diffusion. The results demonstrate that the incorporation of Chol into 1,2-dioleoyl-<i>sn-glycero</i>-3-phosphocholine (DOPC) membranes decelerates lipid diffusion, with a positive correlation observed between the degree of deceleration and the mole ratio of Chol molecules. Across all these systems, lipid diffusion consistently adheres to the continuous time random walk (CTRW) model, indicating lipid entrapment resulting from specific molecular interactions. Conversely, micrometer-scale spatial confinement induced by phase separation not only reduces the diffusion rate of DOPC molecules but also triggers a transition from CTRW to fractional Brownian motion (fBM) or random walk on a fractal (RWF) mode within a confinement width range of 6.3-5.4 μm, suggesting a crowded microenvironment. In living cell membranes, this transformation in lipid diffusion is observed following Chol depletion, implying that lipid raft disruption leads to increased crowding within the lipid microenvironment. This study enhances our understanding of the relationship between lipid diffusion and membrane microenvironment across different spatial scales while providing insights into characterizing spatially heterogeneous structures within cell membranes from the perspective of lipid diffusion.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148680","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 and Swelling Properties of Biodegradable Cross-Linked Polyurethanes by Means of Nuclear Magnetic Resonance.","authors":"Vanda Papp, Bence Vadkerti, István Bányai, Sándor Kéki, Mónika Kéri","doi":"10.1021/acs.jpcb.5c01046","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c01046","url":null,"abstract":"<p><p>In this study, the swelling properties and structural changes during the interaction with liquid media of biodegradable cross-linked polyurethanes promising from medical and environmental points of view are reported. To characterize the polyurethane samples, containing sucrose as cross-linking agent in different concentrations, in the dry state, and swollen in water and dimethyl sulfoxide (DMSO), low- and high-field liquid-phase NMR spectroscopic methods, such as relaxometry, diffusometry, and cryoporometry, were applied. Based on the NMR relaxation features of the swelling liquids and the swollen cross-linked polymers, the difference in the interaction with the two liquids was evaluated; furthermore, the rigid and mobile domains in the amorphous part of the polymer were successfully identified. The change of their ratio with the sucrose content and the restricted diffusion of DMSO in the swollen polymer network reflected the cross-link density and highlighted the role of dangling chains. The swelling process in DMSO was followed by the change of the <i>T</i>₂ relaxation of the infiltrating liquid in time and was described by the second-order kinetic model with a suggested, detailed swelling mechanism. Cryoporometry measurements enlightened the effect of swelling on the size change of the liquid domains in the cross-linked structure.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141025","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":"Interactions of Micro- and Nanoplastics with Biomolecules: From Public Health to Protein Corona Effect and Beyond.","authors":"Tao Zhang, Zi Wang, Yue Wu, Sihao Zhu, Jiaye Su","doi":"10.1021/acs.jpcb.5c00416","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c00416","url":null,"abstract":"<p><p>Micro- and nanoplastics (M/NPs), as ubiquitous global environmental pollutants, have garnered increasing attention due to their pervasive presence. These particles can interact with biological molecules through various mechanisms, subsequently inducing potential toxic effects on living organisms. This review investigates the hazards of M/NPs and their interactions with biological membranes and proteins, focusing on their interaction mechanisms and potential effects on biomolecular structure and function. Specifically, we summarize the exposure pathways and potential harms of M/NPs, which can enter the human body through ingestion, inhalation, and skin contact, potentially causing toxicity, inflammation responses, oxidative stress, and endocrine disruption. Additionally, we highlight the interaction between M/NPs and biological membranes, which can induce structural changes, including membrane thickening, increased fluidity, and pore formation, thereby compromising membrane integrity and affecting cellular health. Besides, we emphasize the interaction between M/NPs and proteins, suggesting that protein structural changes and corona formation can influence oxidative stress responses and cytotoxicity, thereby impacting cellular functions and viability. Ultimately, suggestions and outlooks for further research are proposed. Overall, this review systematically summarizes current research on the interactions between M/NPs and biomolecules, including their mechanisms and biological effects, providing researchers with a comprehensive understanding of the field.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141021","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":"Formation and Disruption of Hydrogen Bond in 1-Ethyl-3-methylimidazolium Ethylsulfate and Glycerol Binary Mixtures: A Molecular Perspective.","authors":"Md Ahad Ali, Md Abu Bin Hasan Susan","doi":"10.1021/acs.jpcb.5c01519","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c01519","url":null,"abstract":"<p><p>This study focuses on the hydrogen bonding interactions that govern the physicochemical properties of the binary mixtures of 1-ethyl-3-methylimidazolium ethylsulfate ([C₂mim]C₂H₅SO₄) and glycerol. Various thermodynamic properties of [C₂mim]C₂H₅SO₄ and glycerol mixtures were investigated by using density and viscosity across a range of compositions and temperatures, while structural properties were explored by using temperature-dependent near-infrared (NIR) spectroscopy, two-dimensional (2D) correlation spectroscopy, and principal component analyses (PCA). In order to better understand hydrogen bonding interactions, both analyses were employed. The NIR spectroscopic analysis shows the presence of various types of hydrogen-bonded clusters in the structure of glycerol and a strong hydrogen bond between the hydrogen of the imidazole ring and the oxygen of ethylsulfate anions. In the binary mixtures, hydrogen-bonded clusters of glycerol were sustained upon addition of [C₂mim]C₂H₅SO₄ up to a mole fraction of 0.6. Further addition of [C₂mim]C₂H₅SO₄ causes breakdown of the cluster of glycerol and forms solvated ions of [C₂mim]C₂H₅SO_4. The variation of excess molar volume, dynamic viscosity deviation, excess molar Gibbs free energy of activation, and thermodynamic activation parameters also show transitions at this particular composition. Hence, the dynamic interaction between the formation and disruption of hydrogen bonds in these compounds controls the thermodynamic properties, which is the key factor to apply this binary system in various fields.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126234","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":"Computing the pH-Dependent Thermodynamics of the Allostery between Dimerization and Palmitate Binding in β-Lactoglobulin.","authors":"Lucie da Rocha, Sara R R Campos, António M Baptista","doi":"10.1021/acs.jpcb.5c01119","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c01119","url":null,"abstract":"<p><p>The study of pH-dependent allosteric processes presents a significant challenge, both experimentally and computationally. In this work, we apply the constant-pH molecular dynamics method to explore an interesting case of allostery involving protein-ligand binding and dimerization. As a model system, we use β-lactoglobulin (BLG), a small protein from bovine milk known to dimerize and bind palmitic acid in a hydrophobic pocket─both processes sensitive to pH. This study focuses on the holo form of BLG, and, when combined with our previous study of the apo form (da Rocha et al. <i>J. Chem. Theory Comput.</i> <b>2022</b> 18, 1982), completes the thermodynamic cycle of the allosteric process. The corresponding pH-dependent free energy profiles are obtained through the use of a thermodynamic linkage relation, avoiding the need of performing heavy computational calculations. Dimerization is found to be more favorable near the isoionic point, as observed in the apo form. Palmitate binding is found to be more favorable around pH 6-7, a biologically relevant pH range at which the gate covering the binding site is known to open. A pH-dependent measure of allosteric coupling is computed, showing that ligand binding and dimerization exhibit an antagonist relationship within the studied pH range of 3-8, with binding destabilizing dimerization and vice versa.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126229","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}