Monobody, an antibody-mimetic protein, regulates enzyme functions via protein-protein interactions. This study examines the binding mechanisms of monobodies for adenylate kinase (Adk), focusing on thermodynamics and structural aspects. The calorimetric and X-ray crystallographic analyses for CL-1, a monobody specific to the CLOSED form of Adk, showed that CL-1 binds to the CORE domain in an enthalpy-driven manner, forming hydrogen bonds and a cation-π interaction at the interface with Adk. In contrast, OP-4, an OPEN-form-specific monobody, exhibited entropy-driven binding. The 1H-15N 2D nuclear magnetic resonance (NMR) and 31P-NMR studies showed the conformational perturbation to Adk by OP-4, while substrate access remains intact. The different thermodynamic and structural effects between CL-1 and OP-4 highlight the diversified binding mechanisms in monobodies.
{"title":"Binding mechanism of adenylate kinase-specific monobodies","authors":"Takashi, Matsuo, Ibuki, Nakamura, Hiroshi, Amesaka, Satoshi, Nagao, Shigeru, Negi, Shun-ichi, Tanaka","doi":"10.26434/chemrxiv-2024-7591m","DOIUrl":"https://doi.org/10.26434/chemrxiv-2024-7591m","url":null,"abstract":"Monobody, an antibody-mimetic protein, regulates enzyme functions via protein-protein interactions. This study examines the binding mechanisms of monobodies for adenylate kinase (Adk), focusing on thermodynamics and structural aspects. The calorimetric and X-ray crystallographic analyses for CL-1, a monobody specific to the CLOSED form of Adk, showed that CL-1 binds to the CORE domain in an enthalpy-driven manner, forming hydrogen bonds and a cation-π interaction at the interface with Adk. In contrast, OP-4, an OPEN-form-specific monobody, exhibited entropy-driven binding. The 1H-15N 2D nuclear magnetic resonance (NMR) and 31P-NMR studies showed the conformational perturbation to Adk by OP-4, while substrate access remains intact. The different thermodynamic and structural effects between CL-1 and OP-4 highlight the diversified binding mechanisms in monobodies.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Atomically precise gold nanoclusters have shown great promise as model elctrocatalysts in pivotal electrocatalytic processes such as hydrogen evolution reaction (HER) and carbon dioxide reduction reaction (CO2RR). Although the influence of ligands on the electronic properties of these nanoclusters are well acknowledged, the ligand effects on their electrocatalytic performances have been rarely explored. Herein, using [Au25(SR)18]- nanocluster as the prototype model, we demonstrated the importance of ligand hydrophilicity versus hydrophobicity in modulating the interface dynamics and electrocatalytic performance. Our first-principle computations revealed that Au25 protected by hydrophilic -SCH2COOH ligands dictates faster kinetics in stripping the thiolate ligand and exhibits better HER activity due to enhanced proton transfer facilitated by boosted interface hydrogen bonding. Conversely, Au25 protected by hydrophobic -SCH2CH3 ligands demonstrates enhanced CO2RR performance by minimizing water interference to stabilize the key *COOH intermediate and lower the barrier for CO formation. Experimental validation using synthesized [Au25(MPA)18]- (MPA=Mercaptopropionic acid) and [Au25(SC6H13)18]- confirms these findings, where [Au25(MPA)18]- exhibits better activity and stability in HER, while [Au25(SC6H13)18]- achieves higher Faradaic efficiency and current density in CO2RR. The mechanistic insights in this study provide valuable guidance for the rational design of surface microenvironment in efficient nanocatalysts for sustainable energy applications.
{"title":"Ligand-induced Changes in the Electrocatalytic Activity of Atomically Precise Au₂₅ Nanoclusters","authors":"Qing, Tang, Lipan, Luo, Xia, Zhou, Yuping, Chen, Fang, Sun, Likai, Wang","doi":"10.26434/chemrxiv-2024-t9f58","DOIUrl":"https://doi.org/10.26434/chemrxiv-2024-t9f58","url":null,"abstract":"Atomically precise gold nanoclusters have shown great promise as model elctrocatalysts in pivotal electrocatalytic processes such as hydrogen evolution reaction (HER) and carbon dioxide reduction reaction (CO2RR). Although the influence of ligands on the electronic properties of these nanoclusters are well acknowledged, the ligand effects on their electrocatalytic performances have been rarely explored. Herein, using [Au25(SR)18]- nanocluster as the prototype model, we demonstrated the importance of ligand hydrophilicity versus hydrophobicity in modulating the interface dynamics and electrocatalytic performance. Our first-principle computations revealed that Au25 protected by hydrophilic -SCH2COOH ligands dictates faster kinetics in stripping the thiolate ligand and exhibits better HER activity due to enhanced proton transfer facilitated by boosted interface hydrogen bonding. Conversely, Au25 protected by hydrophobic -SCH2CH3 ligands demonstrates enhanced CO2RR performance by minimizing water interference to stabilize the key *COOH intermediate and lower the barrier for CO formation. Experimental validation using synthesized [Au25(MPA)18]- (MPA=Mercaptopropionic acid) and [Au25(SC6H13)18]- confirms these findings, where [Au25(MPA)18]- exhibits better activity and stability in HER, while [Au25(SC6H13)18]- achieves higher Faradaic efficiency and current density in CO2RR. The mechanistic insights in this study provide valuable guidance for the rational design of surface microenvironment in efficient nanocatalysts for sustainable energy applications.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":"74 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Herein, we investigate the photoactivity of four NiII tolyl chloride complexes supported by either the bulky, bidentate [2.2]pyridinophane (HN2) ligand or the traditional 2,2′-bipyridine (tBubpy) ligand. Despite a change in ligand framework, we observe comparable quantum yields for the photodegradation of all four NiII complexes but do see changes in their affinity for side reactivity and stabilization of photogenerated NiI monomeric species. Additionally, we show that tBubpyNi(tolyl)Cl compounds are not bench-stable, while also observing side reactivity that leads to C-O bond formation and C-C bond formation. By varying the location of the methyl on the tolyl group, we can further perturb the quantum yield of the compounds and the extent of their side reactivity. Time-dependent density functional theory (TDDFT) and ab initio modeling (CASSCF) reveal that a smaller HOMO/LUMO gap and a more energetically accessible tetrahedral-geometry triplet state correlates with increased quantum yields and O2 side-reactivity. By leveraging our HN2 ligand, a bidentate ligand that hinders axial interactions around the nickel center, the radical side reactivity is limited. This study of this new bidentate pyridinophane ligand highlights how photoactivity is affected by the steric environment around the Ni center, and that such photoactivity is not unique to bipyridyl-supported Ni compounds.
在本文中，我们研究了四种由笨重的双齿[2.2]吡啶磷烷（HN2）配体或传统的 2,2′-联吡啶（tBubpy）配体支持的 NiII 甲酰氯配合物的光活性。尽管配体框架发生了变化，但我们观察到所有四种 NiII 复合物的光降解量子产率相当，但它们对副反应的亲和力和光生 NiI 单体物种的稳定性确实发生了变化。此外，我们还发现 tBubpyNi（甲苯基）Cl 复合物并不稳定，同时还观察到了导致 C-O 键形成和 C-C 键形成的侧反应性。通过改变甲苯基上甲基的位置，我们可以进一步扰乱化合物的量子产率及其副反应的程度。与时间相关的密度泛函理论（TDDFT）和 ab initio 建模（CASSCF）显示，较小的 HOMO/LUMO 间隙和在能量上更容易进入的四面体几何三重态与量子产率和 O2 副反应性的提高相关。通过利用我们的 HN2 配体（一种阻碍镍中心周围轴向相互作用的双齿配体），自由基的副反应活性受到了限制。对这种新型双齿吡啶配体的研究突出了光活性如何受到镍中心周围立体环境的影响，而且这种光活性并不是双吡啶基支持的镍化合物所独有的。
{"title":"Photochemistry of Ni(II) tolyl chlorides supported by bidentate ligand frameworks","authors":"Liviu, Mirica, Luke, Westawker, Bailey, Bouley, Josh, Vura-Weis","doi":"10.26434/chemrxiv-2024-d6sj9","DOIUrl":"https://doi.org/10.26434/chemrxiv-2024-d6sj9","url":null,"abstract":"Herein, we investigate the photoactivity of four NiII tolyl chloride complexes supported by either the bulky, bidentate [2.2]pyridinophane (HN2) ligand or the traditional 2,2′-bipyridine (tBubpy) ligand. Despite a change in ligand framework, we observe comparable quantum yields for the photodegradation of all four NiII complexes but do see changes in their affinity for side reactivity and stabilization of photogenerated NiI monomeric species. Additionally, we show that tBubpyNi(tolyl)Cl compounds are not bench-stable, while also observing side reactivity that leads to C-O bond formation and C-C bond formation. By varying the location of the methyl on the tolyl group, we can further perturb the quantum yield of the compounds and the extent of their side reactivity. Time-dependent density functional theory (TDDFT) and ab initio modeling (CASSCF) reveal that a smaller HOMO/LUMO gap and a more energetically accessible tetrahedral-geometry triplet state correlates with increased quantum yields and O2 side-reactivity. By leveraging our HN2 ligand, a bidentate ligand that hinders axial interactions around the nickel center, the radical side reactivity is limited. This study of this new bidentate pyridinophane ligand highlights how photoactivity is affected by the steric environment around the Ni center, and that such photoactivity is not unique to bipyridyl-supported Ni compounds.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The discovery of novel natural products (NPs) from diverse microorganisms is essential for advancing drug discovery. In this study, a chemical approach was employed for NP exploration using the genus Paraconiothyrium sp. isolated from the root soil of Ficus microcarpa on Noho Island, Okinawa. Consequently, we isolated five compounds, including a new chromone, nohocumone (1), as well as four known compounds, known chromone (2), 10-norparvulenone (3), sclerotinin A (4), and calbistrin A (5), from the culture broth of Paraconiothyrium sp. FKR-0637. The planar structure of 1 were elucidated using 1D and 2D NMR analyses, HR-ESI-MS, and chemical derivatization. Chlorinated chromone 1 is a novel compound that was not previously isolated from Paraconiothyrium sp. These results contribute to expanding the structural diversity and collection of NPs that can be obtained from the culture broths of Paraconiothyrium sp.
{"title":"A Chemical Investigation Approach of the Paraconiothyrium sp. FKR-0637 Fungal Strain Enables the Isolation of the New Chlorinated Chromone, Nohocumone","authors":"Akihiro, Sugawara, Haruki, Azami, Yoshihiro, Watanabe, Takahito, Ouchi, Mika, Watabe, Hiroki, Kojima, Yui, Hirano, Saki, Owada, Toshiyuki, Tokiwa, Mayuka, Higo, Kenichi, Nonaka, Toshiaki, Teruya, Hideaki, Hanaki, Masato, Iwatsuki","doi":"10.26434/chemrxiv-2024-ks826-v2","DOIUrl":"https://doi.org/10.26434/chemrxiv-2024-ks826-v2","url":null,"abstract":"The discovery of novel natural products (NPs) from diverse microorganisms is essential for advancing drug discovery. In this study, a chemical approach was employed for NP exploration using the genus Paraconiothyrium sp. isolated from the root soil of Ficus microcarpa on Noho Island, Okinawa. Consequently, we isolated five compounds, including a new chromone, nohocumone (1), as well as four known compounds, known chromone (2), 10-norparvulenone (3), sclerotinin A (4), and calbistrin A (5), from the culture broth of Paraconiothyrium sp. FKR-0637. The planar structure of 1 were elucidated using 1D and 2D NMR analyses, HR-ESI-MS, and chemical derivatization. Chlorinated chromone 1 is a novel compound that was not previously isolated from Paraconiothyrium sp. These results contribute to expanding the structural diversity and collection of NPs that can be obtained from the culture broths of Paraconiothyrium sp.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":"44 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-13DOI: 10.26434/chemrxiv-2024-mfpcn-v2
Dhiman, Ray, Valerio, Rizzi
We introduce an enhanced sampling algorithm to obtain converged free energy landscapes of molecular rare events, even when the collective variable (CV) used for biasing is not optimal. Our approach samples a time-dependent target distribution by combining the On-the-fly probability enhanced sampling (OPES) and its exploratory variant, OPES Explore (OPESe). This promotes more transitions between the relevant metastable states and accelerates the convergence speed of the free energy estimate. This is accomplished We demonstrate the successful application of this combined algorithm on the two-dimensional Wolfe-Quapp potential, millisecond timescale ligand-receptor binding in trypsin-benzamidine complex, and folding-unfolding transitions in chignolin mini-protein. Our proposed algorithm can compute accurate free energies at an affordable computational cost and is robust in terms of the choice of collective variables, making it particularly promising for the simulation of complex biomolecular systems.
我们介绍了一种增强采样算法，即使用于偏置的集体变量（CV）不是最佳的，也能获得收敛的分子稀有事件自由能谱。我们的方法通过结合即时概率增强采样（OPES）及其探索性变体 OPES 探索（OPESe），对随时间变化的目标分布进行采样。这促进了相关可变状态之间的更多转换，并加快了自由能估计的收敛速度。我们在二维 Wolfe-Quapp 势、胰蛋白酶-苯甲脒复合物中毫秒级配体-受体结合以及木犀草素小蛋白的折叠-解折叠跃迁中演示了这一组合算法的成功应用。我们提出的算法能以可承受的计算成本计算出精确的自由能，并且在集体变量的选择上具有鲁棒性，因此特别适合模拟复杂的生物分子系统。
{"title":"Enhanced Sampling with Sub-optimal Collective Variables: Reconciling Accuracy and Convergence Speed","authors":"Dhiman, Ray, Valerio, Rizzi","doi":"10.26434/chemrxiv-2024-mfpcn-v2","DOIUrl":"https://doi.org/10.26434/chemrxiv-2024-mfpcn-v2","url":null,"abstract":"We introduce an enhanced sampling algorithm to obtain converged free energy landscapes of molecular rare events, even when the collective variable (CV) used for biasing is not optimal. Our approach samples a time-dependent target distribution by combining the On-the-fly probability enhanced sampling (OPES) and its exploratory variant, OPES Explore (OPESe). This promotes more transitions between the relevant metastable states and accelerates the convergence speed of the free energy estimate. This is accomplished We demonstrate the successful application of this combined algorithm on the two-dimensional Wolfe-Quapp potential, millisecond timescale ligand-receptor binding in trypsin-benzamidine complex, and folding-unfolding transitions in chignolin mini-protein. Our proposed algorithm can compute accurate free energies at an affordable computational cost and is robust in terms of the choice of collective variables, making it particularly promising for the simulation of complex biomolecular systems.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The nanometric ions (nano-ions) SiW12O404- (SiW) and B(C6H5)4- (BPh4) are considered as a superchaotropic and a hydro-phobic ion, respectively, in extension to the chaotropic side of the Hofmeister series. A distinction between chaotropic, superchaotropic and hydrophobic ions, however, has not been presented so far. Herein, we show by measurement of the viscosity B-coefficient of SiW (and other nano-ions) and of ion binding to the non-ionic polymer hydroxypropylcellulose (HPC), how chaotropic, superchaotropic and hydrophobic ions can be unambiguously distinguished. The viscosity B-coefficient of the superchaotropic SiW is positive as for hydrophobic ions, and distinct from classical chaotropic ions with a negative B-coefficient. In HPC-solution, BPh4 and SiW bind to the polymer, dramatically increasing the viscosity and the cloud point. Heating induces characteristically distinct responses for the two nano-ions: The viscosity rises for BPh4 and decreases for SiW. These effects are related to nano-ion induced aggregation and electric charging of HPC, which, upon heating, become stronger for BPh4 and weaker for SiW as shown by Small Angle X-ray and Neutron Scattering. 1H-Nuclear Magnetic Resonance and Isothermal Titration Calorimetry showed that the structural effects are linked to binding thermodynamics. Upon heating, the binding constant decreases for SiW and increases for BPh4 arising respectively from an enthalpically favorable, exothermic, chaotropic driving force or an enthalpically unfavorable, endothermic, hydropho-bic driving force. Combining the viscosity B-coefficient and sign of the binding enthalpy enables distinguishing cha-otropic, superchaotropic and hydrophobic ions. Importantly, superchaotropic binding can be stronger or weaker than hydrophobic binding depending on the temperature. Ion hydration and binding are demonstrated as powerful tools to tune polymer solution properties.
纳米离子 SiW12O404- (SiW) 和 B(C6H5)4- (BPh4) 分别被认为是超各向同性离子和疏水性离子，是霍夫迈斯特（Hofmeister）系列中各向同性离子的延伸。然而，迄今为止还没有人提出过混沌离子、超混沌离子和疏水离子之间的区别。在此，我们通过测量 SiW（和其他纳米离子）的粘度 B 系数以及离子与非离子聚合物羟丙基纤维素（HPC）的结合情况，展示了如何明确区分各向混沌离子、超各向混沌离子和疏水离子。与疏水离子一样，超各向同性 SiW 的粘度 B 系数为正，而传统的各向同性离子的粘度 B 系数为负。在 HPC 溶液中，BPh4 和 SiW 与聚合物结合，大大增加了粘度和浊点。加热会导致两种纳米离子产生截然不同的反应：BPh4 的粘度上升，SiW 的粘度下降。小角 X 射线和中子散射显示，这些效应与纳米离子诱导的 HPC 聚合和电荷有关，加热后，BPh4 的聚合和电荷变得更强，而 SiW 的聚合和电荷变得更弱。1H-核磁共振和等温滴定量热法表明，结构效应与结合热力学有关。加热时，SiW 的结合常数会降低，而 BPh4 的结合常数会升高，这分别是由于焓有利、放热、混沌驱动力或焓不利、内热、亲水驱动力造成的。结合粘度 B 系数和结合焓的符号，可以区分混沌各向同性离子、超混沌各向同性离子和疏水离子。重要的是，超各向同性结合可能比疏水结合强，也可能比疏水结合弱，这取决于温度。离子水合和结合被证明是调整聚合物溶液特性的有力工具。
{"title":"Chaotropic or Hydrophobic Effect: Distinct binding signatures of nano-ions to a non-ionic polymer","authors":"Max, Hohenschutz, Carlos Gonzalez, Lopez, Jasmin, Simons, Hannes, Luhmann, Martin, Dulle","doi":"10.26434/chemrxiv-2024-hkjpk","DOIUrl":"https://doi.org/10.26434/chemrxiv-2024-hkjpk","url":null,"abstract":"The nanometric ions (nano-ions) SiW12O404- (SiW) and B(C6H5)4- (BPh4) are considered as a superchaotropic and a hydro-phobic ion, respectively, in extension to the chaotropic side of the Hofmeister series. A distinction between chaotropic, superchaotropic and hydrophobic ions, however, has not been presented so far. Herein, we show by measurement of the viscosity B-coefficient of SiW (and other nano-ions) and of ion binding to the non-ionic polymer hydroxypropylcellulose (HPC), how chaotropic, superchaotropic and hydrophobic ions can be unambiguously distinguished. The viscosity B-coefficient of the superchaotropic SiW is positive as for hydrophobic ions, and distinct from classical chaotropic ions with a negative B-coefficient. In HPC-solution, BPh4 and SiW bind to the polymer, dramatically increasing the viscosity and the cloud point. Heating induces characteristically distinct responses for the two nano-ions: The viscosity rises for BPh4 and decreases for SiW. These effects are related to nano-ion induced aggregation and electric charging of HPC, which, upon heating, become stronger for BPh4 and weaker for SiW as shown by Small Angle X-ray and Neutron Scattering. 1H-Nuclear Magnetic Resonance and Isothermal Titration Calorimetry showed that the structural effects are linked to binding thermodynamics. Upon heating, the binding constant decreases for SiW and increases for BPh4 arising respectively from an enthalpically favorable, exothermic, chaotropic driving force or an enthalpically unfavorable, endothermic, hydropho-bic driving force. Combining the viscosity B-coefficient and sign of the binding enthalpy enables distinguishing cha-otropic, superchaotropic and hydrophobic ions. Importantly, superchaotropic binding can be stronger or weaker than hydrophobic binding depending on the temperature. Ion hydration and binding are demonstrated as powerful tools to tune polymer solution properties.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":"100 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-13DOI: 10.26434/chemrxiv-2024-78w36-v2
Han-Chung, Chang, Yi-Pei, Li, Ming-Hsuan, Tsai
Accurately predicting activation energies is crucial for understanding chemical reactions and modeling complex reaction systems. However, the high computational cost of quantum chemistry methods often limits the feasibility of large-scale studies, leading to a scarcity of high-quality activation energy data. In this work, we explore and compare three innovative approaches—transfer learning, delta learning, and feature engineering—to enhance the accuracy of activation energy predictions using graph neural networks, specifically focusing on methods that incorporate low-cost, low-level computational data. Using the Chemprop model, we systematically evaluated how these methods leverage data from semiempirical quantum mechanical (SQM) calculations to improve predictions. Delta learning, which adjusts low-level SQM activation energies to align with high-level CCSD(T)-F12a targets, emerged as the most effective method, achieving high accuracy with substantially reduced high-level data requirements. Notably, delta learning trained with just 20%–30% of high-level data matched or exceeded the performance of other methods trained with full datasets, making it advantageous in data-scarce scenarios. However, its reliance on transition state searches imposes significant computational demands during model application. Transfer learning, which pretrains models on large datasets of low-level data, provided mixed results, particularly when there was a mismatch in the reaction distributions between the training and target datasets. Feature engineering, which involves adding computed molecular properties as input features, showed modest gains, particularly when incorporating thermodynamic properties. Our study highlights the trade-offs between accuracy and computational demand in selecting the best approach for enhancing activation energy predictions. These insights provide valuable guidelines for researchers aiming to apply machine learning in chemical reaction engineering, helping to balance accuracy with resource constraints.
{"title":"Enhancing Activation Energy Predictions under Data Constraints Using Graph Neural Networks","authors":"Han-Chung, Chang, Yi-Pei, Li, Ming-Hsuan, Tsai","doi":"10.26434/chemrxiv-2024-78w36-v2","DOIUrl":"https://doi.org/10.26434/chemrxiv-2024-78w36-v2","url":null,"abstract":"Accurately predicting activation energies is crucial for understanding chemical reactions and modeling complex reaction systems. However, the high computational cost of quantum chemistry methods often limits the feasibility of large-scale studies, leading to a scarcity of high-quality activation energy data. In this work, we explore and compare three innovative approaches—transfer learning, delta learning, and feature engineering—to enhance the accuracy of activation energy predictions using graph neural networks, specifically focusing on methods that incorporate low-cost, low-level computational data. Using the Chemprop model, we systematically evaluated how these methods leverage data from semiempirical quantum mechanical (SQM) calculations to improve predictions. Delta learning, which adjusts low-level SQM activation energies to align with high-level CCSD(T)-F12a targets, emerged as the most effective method, achieving high accuracy with substantially reduced high-level data requirements. Notably, delta learning trained with just 20%–30% of high-level data matched or exceeded the performance of other methods trained with full datasets, making it advantageous in data-scarce scenarios. However, its reliance on transition state searches imposes significant computational demands during model application. Transfer learning, which pretrains models on large datasets of low-level data, provided mixed results, particularly when there was a mismatch in the reaction distributions between the training and target datasets. Feature engineering, which involves adding computed molecular properties as input features, showed modest gains, particularly when incorporating thermodynamic properties. Our study highlights the trade-offs between accuracy and computational demand in selecting the best approach for enhancing activation energy predictions. These insights provide valuable guidelines for researchers aiming to apply machine learning in chemical reaction engineering, helping to balance accuracy with resource constraints.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abuse of xylazine is an immediate global public health concern. We report the distinct and measurable colour changes when xylazine is exposed to the Mandelin, Marquis, and Mecke presumptive test reagents. The colour changes observed with xylazine are distinct from those of drugs that give colour changes from the same presumptive tests. Using single image and video analyses, distinctive features of presumptive tests with xylazine help differentiate it from other illicit substances tested under the same conditions, including morphine, fentanyl, heroin, and methamphetamine. Herein, experimental protocols utilising textit{Kineticolor}, a computer vision software, were developed to qualitatively and quantitatively study presumptive tests for xylazine detection. To the best of our knowledge, these findings represent the first presumptive test strategy towards specific, quantifiable, and potentially field-ready detection of xylazine.
{"title":"Presumptive Tests for Xylazine – A Computer Vision Approach","authors":"Marc, Reid, Hui Yun, Chang, Kristin, Donnachie, Timothy J.D., McCabe, Felicity, Carlysle-Davies, Kristin, Ceniccola-Campos, Henry, Barrington","doi":"10.26434/chemrxiv-2024-487ch-v2","DOIUrl":"https://doi.org/10.26434/chemrxiv-2024-487ch-v2","url":null,"abstract":"Abuse of xylazine is an immediate global public health concern. We report the distinct and measurable colour changes when xylazine is exposed to the Mandelin, Marquis, and Mecke presumptive test reagents. The colour changes observed with xylazine are distinct from those of drugs that give colour changes from the same presumptive tests. Using single image and video analyses, distinctive features of presumptive tests with xylazine help differentiate it from other illicit substances tested under the same conditions, including morphine, fentanyl, heroin, and methamphetamine. Herein, experimental protocols utilising textit{Kineticolor}, a computer vision software, were developed to qualitatively and quantitatively study presumptive tests for xylazine detection. To the best of our knowledge, these findings represent the first presumptive test strategy towards specific, quantifiable, and potentially field-ready detection of xylazine.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-13DOI: 10.26434/chemrxiv-2024-2zt43-v2
Ashish, Garg, Himanshu, Mishra, Jayati, Sarkar, Sudip K., Pattanayek
In this study, we develop a comprehensive analytical framework to derive the optimal scaling laws for turbulent flows within tree-like self-similar branching networks, integrating a non-Newtonian power-law fluid model with index $n$. Our analysis encompasses turbulent flows occurring in both smooth and rough tubes under constraints of network's tube-volume and tube surface area. We introduce the non-dimensional conductance parameter $E$ to quantify flow conditions, investigating its variations with diameter ratio $beta$, length ratio $gamma$, branch splitting $N$, and branching generation levels $m$. Our findings reveal a decrease in $E$ with increasing $gamma$, $N$, and $m$, highlighting the influence of these parameters on flow conductance. Under volume constraint, we identify optimal flow conditions for both smooth and rough tube networks, characterized by distinct scaling laws as $ D_{k+1}/D_{k} = beta^* = N^{-(10n+1)/(24n+3)} $, and $D_{k+1}/D_{k} = N^{-3/7} $ (or flow rate proportional to $D_k^{(24n+3)/(10n+1)}$ and $D_k^{7/3}$ ), respectively, where $D_k$ is tube-diameter and $dot{m}_k$ is the mass flow-rate in a branch at the $k_{th}$ level . Notably, the scaling in the rough tube network remains independent of the power-law index $n$, unlike the smooth tube network where it depends on $n$. Similarly, under surface-area constraint, we observe distinct optimal flow conditions for smooth and rough tube networks as with different scaling laws as $D_{k+1}/D_{k} = beta^* = N^{-(10n+1)/(21n+2)} $, and $D_{k+1}/D_{k} = N^{-1/2} $ (or flow rate proportional to $D_k^{(21n+2)/(10n+1)}$ and $D_k^{2}$ ), respectively, again smooth tube network showing dependency on the power-law index $n$. Moreover, we uncover a trend where the scaling exponent slope decreases with increasing $n$ in volume constraint networks, while the opposite holds true for surface-area constraint networks. In conclusion, our research significantly extends the applicability of Murray's Law, offering valuable insights into the design and optimization of branching networks under various constraints and fluid properties. By incorporating non-Newtonian fluid behavior and considering tube-wall characteristics, our findings contribute to enhancing the efficiency and performance of diverse engineering systems involving fluid flow.
{"title":"Scaling Laws for Optimal Turbulent Flow in Tree-Like Networks with Smooth and Rough Tubes and Power-Law Fluids","authors":"Ashish, Garg, Himanshu, Mishra, Jayati, Sarkar, Sudip K., Pattanayek","doi":"10.26434/chemrxiv-2024-2zt43-v2","DOIUrl":"https://doi.org/10.26434/chemrxiv-2024-2zt43-v2","url":null,"abstract":"In this study, we develop a comprehensive analytical framework to derive the optimal scaling laws for turbulent flows within tree-like self-similar branching networks, integrating a non-Newtonian power-law fluid model with index $n$. Our analysis encompasses turbulent flows occurring in both smooth and rough tubes under constraints of network's tube-volume and tube surface area. We introduce the non-dimensional conductance parameter $E$ to quantify flow conditions, investigating its variations with diameter ratio $beta$, length ratio $gamma$, branch splitting $N$, and branching generation levels $m$. Our findings reveal a decrease in $E$ with increasing $gamma$, $N$, and $m$, highlighting the influence of these parameters on flow conductance. Under volume constraint, we identify optimal flow conditions for both smooth and rough tube networks, characterized by distinct scaling laws as $ D_{k+1}/D_{k} = beta^* = N^{-(10n+1)/(24n+3)} $, and $D_{k+1}/D_{k} = N^{-3/7} $ (or flow rate proportional to $D_k^{(24n+3)/(10n+1)}$ and $D_k^{7/3}$ ), respectively, where $D_k$ is tube-diameter and $dot{m}_k$ is the mass flow-rate in a branch at the $k_{th}$ level . Notably, the scaling in the rough tube network remains independent of the power-law index $n$, unlike the smooth tube network where it depends on $n$. Similarly, under surface-area constraint, we observe distinct optimal flow conditions for smooth and rough tube networks as with different scaling laws as $D_{k+1}/D_{k} = beta^* = N^{-(10n+1)/(21n+2)} $, and $D_{k+1}/D_{k} = N^{-1/2} $ (or flow rate proportional to $D_k^{(21n+2)/(10n+1)}$ and $D_k^{2}$ ), respectively, again smooth tube network showing dependency on the power-law index $n$. Moreover, we uncover a trend where the scaling exponent slope decreases with increasing $n$ in volume constraint networks, while the opposite holds true for surface-area constraint networks. In conclusion, our research significantly extends the applicability of Murray's Law, offering valuable insights into the design and optimization of branching networks under various constraints and fluid properties. By incorporating non-Newtonian fluid behavior and considering tube-wall characteristics, our findings contribute to enhancing the efficiency and performance of diverse engineering systems involving fluid flow.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":"63 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The application of NMR to large RNAs has been limited by the inability to perform heteronuclear correlation experiments essential for resolving overlapping 1H NMR signals, determining inter-proton distance restraints and inter-helical orientations for structure calcula-tions, and evaluating conformational dynamics. Approaches exploiting 1H-13C correlations that are routinely applied to proteins and small RNAs of ~60 nucleotides or fewer are impractical for larger RNAs due to rapid dipolar relaxation of protons by their attached car-bons. Here we report a 2H-enhanced, 1H-15N correlation approach that enables atom-specific NMR characterization of much larger RNAs. Purine H8 transverse relaxation rates are reduced ~20-fold with ribose perdeuteration, enabling efficient magnetization transfer via two-bond 1H-15N couplings. We focus on H8-N9 correlation spectra which benefit from favorable N9 chemical shift anisotropy. Chemical shift assignment is enabled by retention of protons at the C1′ position, which allow measurement of two-bond H1′-N9 and through-space H1′-H8 correlations with only a minor effect on H8 relaxation. The approach is demonstrated for the 232 nucleotide HIV-1 Rev response element, where chemical shift assignments, 15N-edited nuclear Overhauser effects, and 1H-15N residual dipolar couplings are readily obtained from sensitive, high-resolution spectra. Heteronuclear correlated NMR methods that have been essential for the study of proteins can now be extended to RNAs of at least 78 kDa.
{"title":"Relaxation optimized heteronuclear experiments for extending the size limit of RNA nuclear magnetic resonance","authors":"Jan, Marchant, Aarsh, Shah, Heer, Patel, Arjun, Kanjarpane, Michael, Summers","doi":"10.26434/chemrxiv-2024-qs8d7-v2","DOIUrl":"https://doi.org/10.26434/chemrxiv-2024-qs8d7-v2","url":null,"abstract":"The application of NMR to large RNAs has been limited by the inability to perform heteronuclear correlation experiments essential for resolving overlapping 1H NMR signals, determining inter-proton distance restraints and inter-helical orientations for structure calcula-tions, and evaluating conformational dynamics. Approaches exploiting 1H-13C correlations that are routinely applied to proteins and small RNAs of ~60 nucleotides or fewer are impractical for larger RNAs due to rapid dipolar relaxation of protons by their attached car-bons. Here we report a 2H-enhanced, 1H-15N correlation approach that enables atom-specific NMR characterization of much larger RNAs. Purine H8 transverse relaxation rates are reduced ~20-fold with ribose perdeuteration, enabling efficient magnetization transfer via two-bond 1H-15N couplings. We focus on H8-N9 correlation spectra which benefit from favorable N9 chemical shift anisotropy. Chemical shift assignment is enabled by retention of protons at the C1′ position, which allow measurement of two-bond H1′-N9 and through-space H1′-H8 correlations with only a minor effect on H8 relaxation. The approach is demonstrated for the 232 nucleotide HIV-1 Rev response element, where chemical shift assignments, 15N-edited nuclear Overhauser effects, and 1H-15N residual dipolar couplings are readily obtained from sensitive, high-resolution spectra. Heteronuclear correlated NMR methods that have been essential for the study of proteins can now be extended to RNAs of at least 78 kDa.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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