The Journal of Physical Chemistry B最新文献

{"title":"Multiscale Simulations and Profiling of Human Thymidine Phosphorylase Mutations: Insights into Structural, Dynamics, and Functional Impacts in Mitochondrial Neurogastrointestinal Encephalopathy","authors":"Khushboo Bhagat,&nbsp;Amar Jeet Yadav and Aditya K. Padhi*,&nbsp;","doi":"10.1021/acs.jpcb.5c0077110.1021/acs.jpcb.5c00771","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c00771https://doi.org/10.1021/acs.jpcb.5c00771","url":null,"abstract":"<p >Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare metabolic disorder caused by missense mutations in the <i>TYMP</i> gene, leading to the loss of human thymidine phosphorylase (HTP) activity and subsequent mitochondrial dysfunction. Despite its well-characterized biochemical basis, the molecular mechanisms by which MNGIE-associated mutations alter HTP’s structural stability, dynamics, and substrate (thymidine) binding remain unclear. In this study, we employ a multiscale computational approach, integrating AlphaFold2-based structural modeling, all-atom and coarse-grained molecular dynamics (MD) simulations, protein–ligand (HTP–thymidine) docking, HTP–thymidine complex simulations, binding free-energy landscape analysis, and systematic mutational profiling to investigate the impact of key MNGIE-associated mutations (R44Q, G145R, G153S, K222S, and E289A) on HTP function. Analyses of our long-duration multiscale simulations (comprising 9 μs coarse-grained, 1.2 μs all-atom apo HTP, and 1.2 μs HTP–thymidine complex MD simulations) and physicochemical properties reveal that while wild-type HTP maintains structural integrity and strong thymidine-binding affinity, MNGIE-associated mutations induce substantial destabilization, increased flexibility, and reduced enzymatic efficiency. Free-energy landscape analysis highlights a shift toward less stable conformational states in mutant HTPs, further supporting their functional impairment. Additionally, the G145R mutation introduces steric hindrance at the active site, preventing thymidine binding and causing off-site interactions. These findings not only provide fundamental insights into the physicochemical and dynamic alterations underlying HTP dysfunction in MNGIE but also establish a computational framework for guiding future experimental studies and the rational design of therapeutic interventions aimed at restoring HTP function.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":"129 13","pages":"3366–3384 3366–3384"},"PeriodicalIF":2.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758800","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":"Water Transportation through Nano/Microsized Lipid Protocells with a Significant Deviation from the van't Hoff Osmotic Rule.","authors":"Shujiao Chen, Shuai Zhang, Qunhui Yuan, Wei Gan","doi":"10.1021/acs.jpcb.5c00133","DOIUrl":"10.1021/acs.jpcb.5c00133","url":null,"abstract":"<p><p>Osmotic pressure is known to be an important driving force that induces water transport through membranes, which is crucial for many biophysical processes. Here, we observed that under a relatively low osmotic pressure induced by sugars' protocells (vesicles) with a diameter of ∼110 nm barely shrank. However, NaCl and CaCl₂ at lower concentrations induced a rapid decrease in the vesicle size as evidence of water transportation through the membrane. An additional mechanical pressure resulting from the increase in interfacial tension of the lipid membrane was proposed to be the main driving force of this electrolyte-specific effect. These results indicate that osmotic pressure is not the only driving force of water transport in nano/microsized lipid protocells.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"3103-3108"},"PeriodicalIF":2.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603059","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":"<i>Ab Initio</i> Molecular Dynamics Simulations of Amino Acids and Their Ammonia-Based Analogues in Ammonia.","authors":"Henrik Niemöller, Johannes Ingenmey, Oldamur Hollóczki, Barbara Kirchner","doi":"10.1021/acs.jpcb.4c06751","DOIUrl":"https://doi.org/10.1021/acs.jpcb.4c06751","url":null,"abstract":"<p><p>α-Amino acids are the fundamental building blocks for complex molecular structures within the water-based biochemistry of Earth. In a hypothetical ammonia-based biochemistry, α-amino amidines may serve an equivalent role. In this study, we explore the basic properties of α-amino amidines in comparison to α-amino acids solvated in ammonia, utilizing <i>ab initio</i> molecular dynamics simulations. The investigation of the time-resolved molecular dipole moment reveals, in intricate detail, the relationship among the conformation, state, and magnitude of the dipole moment. Moreover, it allows for the tracking of proton-transfer reactions. In ammonia, α-amino acids tend to adopt an anionic state, with the zwitterionic state still being accessible. In contrast, the α-amino amidines remain neutral. Grotthuss diffusion is induced by the deprotonation of zwitterionic alanine. The charge transferred upon solvation serves as an indicator for the interaction strength between the solute and solvent. It is much stronger for α-amino acids, while, on average, the α-amino amidines exchange no charge with ammonia. The analyses reveal that in terms of structure, anionic α-amino acids behave very similarly to neutral α-amino amidines.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":"129 11","pages":"3007-3017"},"PeriodicalIF":2.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661598","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":"Prospective Evaluation of Structure-Based Simulations Reveal Their Ability to Predict the Impact of Kinase Mutations on Inhibitor Binding.","authors":"Sukrit Singh, Vytautas Gapsys, Matteo Aldeghi, David Schaller, Aziz M Rangwala, Jessica B White, Joseph P Bluck, Jenke Scheen, William G Glass, Jiaye Guo, Sikander Hayat, Bert L de Groot, Andrea Volkamer, Clara D Christ, Markus A Seeliger, John D Chodera","doi":"10.1021/acs.jpcb.4c07794","DOIUrl":"10.1021/acs.jpcb.4c07794","url":null,"abstract":"<p><p>Small molecule kinase inhibitors are critical in the modern treatment of cancers, evidenced by the existence of over 80 FDA-approved small-molecule kinase inhibitors. Unfortunately, intrinsic or acquired resistance, often causing therapy discontinuation, is frequently caused by mutations in the kinase therapeutic target. The advent of clinical tumor sequencing has opened additional opportunities for precision oncology to improve patient outcomes by pairing optimal therapies with tumor mutation profiles. However, modern precision oncology efforts are hindered by lack of sufficient biochemical or clinical evidence to classify each mutation as resistant or sensitive to existing inhibitors. Structure-based methods show promising accuracy in retrospective benchmarks at predicting whether a kinase mutation will perturb inhibitor binding, but comparisons are made by pooling disparate experimental measurements across different conditions. We present the first prospective benchmark of structure-based approaches on a blinded dataset of in-cell kinase inhibitor affinities to Abl kinase mutants using a NanoBRET reporter assay. We compare NanoBRET results to structure-based methods and their ability to estimate the impact of mutations on inhibitor binding (measured as ΔΔ<i>G</i>). Comparing physics-based simulations, Rosetta, and previous machine learning models, we find that structure-based methods accurately classify kinase mutations as inhibitor-resistant or inhibitor-sensitizing, and each approach has a similar degree of accuracy. We show that physics-based simulations are best suited to estimate ΔΔ<i>G</i> of mutations that are distal to the kinase active site. To probe modes of failure, we retrospectively investigate two clinically significant mutations poorly predicted by our methods, T315A and L298F, and find that starting configurations and protonation states significantly alter the accuracy of our predictions. Our experimental and computational measurements provide a benchmark for estimating the impact of mutations on inhibitor binding affinity for future methods and structure-based models. These structure-based methods have potential utility in identifying optimal therapies for tumor-specific mutations, predicting resistance mutations in the absence of clinical data, and identifying potential sensitizing mutations to established inhibitors.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"2882-2902"},"PeriodicalIF":2.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575642","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":"Research at Predominately Undergraduate Institutions Published Recently in <i>The Journal of Physical Chemistry A, B,</i> and <i>C</i>.","authors":"George C Shields","doi":"10.1021/acs.jpcb.5c00978","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c00978","url":null,"abstract":"","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":"129 11","pages":"2811-2814"},"PeriodicalIF":2.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661604","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":"Research at Predominately Undergraduate Institutions Published Recently in The Journal of Physical Chemistry A, B, and C","authors":"George C. Shields*,&nbsp;","doi":"10.1021/acs.jpcb.5c0097810.1021/acs.jpcb.5c00978","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c00978https://doi.org/10.1021/acs.jpcb.5c00978","url":null,"abstract":"","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":"129 11","pages":"2811–2814 2811–2814"},"PeriodicalIF":2.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143654316","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":"Thermodynamic Parameter Estimation for Modified Oligonucleotides Using Molecular Dynamics Simulations.","authors":"Soon Woo Park, Junehawk Lee, Jung Woo Park, Moon Ki Kim, Sangjae Seo","doi":"10.1021/acs.jpcb.4c08344","DOIUrl":"10.1021/acs.jpcb.4c08344","url":null,"abstract":"<p><p>This study investigates the thermodynamic parameters of 1300 RNA/DNA hybrid duplexes, including both natural and chemically modified forms, using molecular dynamics (MD) simulations. Modified duplexes consist of phosphorothioate (PS) backbones and 2'-<i>O</i>-methoxyethyl (MOE) modifications, both commonly used in therapeutic oligonucleotides. Hybridization enthalpy and entropy were calculated from MD trajectories using molecular mechanics Poisson-Boltzmann surface area (MMPBSA) and molecular mechanics generalized Born surface area (MMGBSA) approaches. To address discrepancies with experimental data, we established empirical relationships by comparing calculated values with known experimental results of natural hybrid duplexes, then extended these relationships to the entire data set. The corrected parameters were subsequently used to generate nearest-neighbor (NN) models, allowing for experimentally reliable melting temperature predictions. In this process, MMGBSA demonstrated superior predictive performance with high convergence and consistency for both natural and modified duplexes. Specifically, MMGBSA captured the stabilizing effects of the MOE modification with minimal bias, while MMPBSA exhibited greater variability and limited reliability. These findings highlight the potential of MMGBSA for accurate thermodynamic modeling of both natural and modified nucleic acids, providing a robust framework and experimentally meaningful insights for applications in nucleic acid-based therapeutic design and biotechnology.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"2934-2945"},"PeriodicalIF":2.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11932115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143571571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined Mutational and Spectroscopic Study on the Calcium-Related Kinetic Effects on the VirChR1 Photocycle.","authors":"Gerrit H U Lamm, Dmitrii Zabelskii, Taras Balandin, Valentin Gordeliy, Josef Wachtveitl","doi":"10.1021/acs.jpcb.4c08416","DOIUrl":"10.1021/acs.jpcb.4c08416","url":null,"abstract":"<p><p>The viral rhodopsin 1 subfamily consists of microbial rhodopsins, such as VirChR1, with a light-gated cation channeling functionality, which is inhibited by calcium. For VirChR1, S14, E54, and N225 have been proposed as key residues for calcium binding. They form a highly conserved SEN-triad in channelrhodopsins near the functionally important central gate. Here, we present a time-resolved UV/vis spectroscopic study on the VirChR1 variants S14A, E54A, and N225A in a calcium-dependent manner. Comparison with the calcium-associated effects observed for the wild type shed light on the role of the respective residues for the calcium interaction. While S14A shows less pronounced, yet similar, signals, indicative of a reduced calcium affinity, E54A exhibits nearly calcium-independent photocycle kinetics, highlighting its crucial role for calcium binding. The N225A variant shows altered photocycle kinetics, in both the absence and presence of calcium, demonstrating its critical role in the formation of the functionally important central gate in VirChR1.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"2946-2957"},"PeriodicalIF":2.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulating Enzyme's Conformational Space: Impact of Substrate Binding, Mode Alteration, and Active Site Mutation in DapC, an Aminotransferase Enzyme of Lysine Biosynthetic Pathway.","authors":"Sourav Manna, Sabyashachi Mishra","doi":"10.1021/acs.jpcb.4c06274","DOIUrl":"10.1021/acs.jpcb.4c06274","url":null,"abstract":"<p><p>The microbial aminotransferase enzyme DapC is vital for lysine biosynthesis in various Gram-positive bacteria, including <i>Mycobacterium tuberculosis</i>. Characterization of the enzyme's conformational dynamics and identifying the key residues for ligand binding are crucial for the development of effective antimicrobials. This study employs atomistic simulations to explore and categorize the dynamics of DapC in comparison to other classes of aminotransferase. DapC undergoes an open-to-closed conformational change upon substrate binding, characterized by the movement of the N-terminal α2 helix, akin to that observed in the class Ib aspartate aminotransferase from <i>Thermus thermophilus</i>. Based on sequence similarity, essential dynamics, and the absence of the characteristic hinge movement, DapC is classified as a class Ib aminotransferase of type-I pyridoxal-5'-phosphate (PLP)-dependent enzyme. In the open state of DapC, two binding modes of glutamate, namely, canonical and alternate, separated by a dihedral rotation, are equally preferred. The closed state prefers the canonical binding mode, which is favorable for catalysis. In the case where the substrate binds in the alternate mode, a low-barrier dihedral rotation generates the canonical mode for efficient catalysis. The presence of two highly conserved residues, Phe14 and Gln31, stabilizes the closed state of substrate-bound DapC. Mutations of these residues disrupt the crucial hydrophobic interactions with the substrate, causing the enzyme to shift to an open state. While Phe14 has a dominant role, Gln31 is less consequential in regulating the conformational change, while the double mutation leads to a rapid conformation change.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"2815-2828"},"PeriodicalIF":2.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057506","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":"Ultrasensitive Differential Scanning Calorimetric (US-DSC) Study of the Thermal-Induced Dynamic Transition Behaviors of PEO–PPO–PEO in Aqueous Solution","authors":"Lin Li,&nbsp;Kang Ni,&nbsp;Lvdan Liu,&nbsp;Yuxia Bai and Yanwei Ding*,&nbsp;","doi":"10.1021/acs.jpcb.4c0824710.1021/acs.jpcb.4c08247","DOIUrl":"https://doi.org/10.1021/acs.jpcb.4c08247https://doi.org/10.1021/acs.jpcb.4c08247","url":null,"abstract":"<p >Temperature-responsive macromolecules can provide insights into the mechanisms of the aggregation and precipitation processes of proteins. In this study, the PEO–PPO–PEO triblock copolymer, Pluronic P123, has been utilized as a protein model to investigate the thermally induced dynamic transition behavior by ultrasensitive differential scanning calorimetry (US-DSC). The results of US-DSC reveal hysteresis in the disaggregation process of P123 micelles. Combined with the particle size distribution, a stepwise disaggregation mechanism is proposed. The disaggregation of P123 micelles in the cooling process involved rod-to-sphere transition, fragmentation, and dissolution of micelles. Moreover, US-DSC results show that both the sphere-to-rod transition and micelle fragmentation are dependent on the scanning rate and reveal the relationship between the dynamic transition and thermodynamic properties of P123. These findings expand the understanding not only of aggregation and disaggregation of P123 in dilute aqueous systems but also of the thermal unfolding and aggregation of proteins.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":"129 13","pages":"3482–3491 3482–3491"},"PeriodicalIF":2.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758803","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}