Pub Date : 2024-09-18DOI: 10.26434/chemrxiv-2024-1dchd
Martin, Rabe, Taritra, Mukherjee
Presence of gold nanoparticles in an aqueous dispersion perturbs water molecules in their vicinity. Such water molecules form what is known as hydration shell and possess different vibrational attributes than those in the bulk dispersion. Raman spectroscopy was utilised to study these hydration shell water molecules around citrate-stabilised gold nanoparticles. Aqueous dilution series of three sizes of gold nanoparticle samples were prepared. Hydration shell spectral response, recovered by applying multivariate curve resolution technique, were compared against the spectra of the bulk phase. Once correlated with an increasing aqueous content in the respective samples, it could be inferred from the comparison that the hydration shell contains a less extensive hydrogen-bonding network with a smaller number of hydrogen-bonding interactions being possible than that in bulk. The results also suggest the hydrogen-bonding network in the hydration shells to be structurally more rigid and stronger, if compared against the intermolecular hydrogen-bonding prevalent in bulk.
{"title":"Hydration Shell Water Surrounding Citrate-Stabilised Gold Nanoparticles","authors":"Martin, Rabe, Taritra, Mukherjee","doi":"10.26434/chemrxiv-2024-1dchd","DOIUrl":"https://doi.org/10.26434/chemrxiv-2024-1dchd","url":null,"abstract":"Presence of gold nanoparticles in an aqueous dispersion perturbs water molecules in their vicinity. Such water molecules form what is known as hydration shell and possess different vibrational attributes than those in the bulk dispersion. Raman spectroscopy was utilised to study these hydration shell water molecules around citrate-stabilised gold nanoparticles. Aqueous dilution series of three sizes of gold nanoparticle samples were prepared. Hydration shell spectral response, recovered by applying multivariate curve resolution technique, were compared against the spectra of the bulk phase. Once correlated with an increasing aqueous content in the respective samples, it could be inferred from the comparison that the hydration shell contains a less extensive hydrogen-bonding network with a smaller number of hydrogen-bonding interactions being possible than that in bulk. The results also suggest the hydrogen-bonding network in the hydration shells to be structurally more rigid and stronger, if compared against the intermolecular hydrogen-bonding prevalent in bulk.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267180","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 : 2024-09-18DOI: 10.26434/chemrxiv-2024-0167h
Subinoy, Rana, Alisha, Kamra, Rohit, Kapila, Bhaskar, Sen
DNA nanotechnology has significantly progressed from basic structural designs to advanced practical applications. The inherent ability of DNA to assemble with small molecules has elevated it to the forefront of biological applications such as biosensing, bioimaging, altering cell behaviour, and therapeutic delivery. Deoxyribozymes (DNAzymes) represent catalytically active DNA molecules, which are essential yet uncommon, making the fabrication of synthetic DNAzymes significant. However, a key challenge in employing DNAzyme nanostructures in biological settings is their susceptibility to degradation by nucleases in the biological milieu. Herein, we introduced a hierarchical assembly of DNA and guanidium containing Pt(II)-complex (Pt G) through supramolecular interactions that display significant resistance to nucleases in human serum. The one-dimensional growth of the supramolecular structures leads to metal-metal bonds that impart luminescence properties with long-lived excited states. Light-mediated singlet oxygen generated from the Pt G·DNA system allows the oxidation of substrates similar to oxidase enzymes. Besides a fundamental understanding of the new hierarchical assembly, the study presents important functional aspects, including the nuclease resistance, robustness, specific oxidase-like function and on-demand light stimulus-dependent activity for practical applications.
从基本结构设计到先进的实际应用，DNA 纳米技术取得了长足的进步。DNA 与小分子组装的固有能力将其提升到生物应用的前沿，如生物传感、生物成像、改变细胞行为和治疗递送。脱氧核糖核酸酶（DNAzymes）是具有催化活性的 DNA 分子，这种分子非常重要，但并不常见，因此制造合成 DNAzymes 意义重大。然而，在生物环境中使用 DNA 酶纳米结构的一个关键挑战是它们容易被生物环境中的核酸酶降解。在这里，我们介绍了一种通过超分子相互作用将DNA和含胍的铂(II)-络合物（铂G）分层组装的方法，这种方法对人血清中的核酸酶具有显著的抗性。超分子结构的一维生长产生了金属-金属键，从而赋予了长寿命激发态的发光特性。由 Pt G-DNA 系统产生的光介导的单线态氧可以使底物氧化，类似于氧化酶。除了从根本上了解新的分层组装外，该研究还介绍了重要的功能方面，包括抗核酸酶性、稳健性、类似于氧化酶的特异性功能，以及在实际应用中随需应变的光刺激活性。
{"title":"Nuclease-resistant photo-responsive synthetic “double-stranded DNAzyme”","authors":"Subinoy, Rana, Alisha, Kamra, Rohit, Kapila, Bhaskar, Sen","doi":"10.26434/chemrxiv-2024-0167h","DOIUrl":"https://doi.org/10.26434/chemrxiv-2024-0167h","url":null,"abstract":"DNA nanotechnology has significantly progressed from basic structural designs to advanced practical applications. The inherent ability of DNA to assemble with small molecules has elevated it to the forefront of biological applications such as biosensing, bioimaging, altering cell behaviour, and therapeutic delivery. Deoxyribozymes (DNAzymes) represent catalytically active DNA molecules, which are essential yet uncommon, making the fabrication of synthetic DNAzymes significant. However, a key challenge in employing DNAzyme nanostructures in biological settings is their susceptibility to degradation by nucleases in the biological milieu. Herein, we introduced a hierarchical assembly of DNA and guanidium containing Pt(II)-complex (Pt G) through supramolecular interactions that display significant resistance to nucleases in human serum. The one-dimensional growth of the supramolecular structures leads to metal-metal bonds that impart luminescence properties with long-lived excited states. Light-mediated singlet oxygen generated from the Pt G·DNA system allows the oxidation of substrates similar to oxidase enzymes. Besides a fundamental understanding of the new hierarchical assembly, the study presents important functional aspects, including the nuclease resistance, robustness, specific oxidase-like function and on-demand light stimulus-dependent activity for practical applications.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267144","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}
PeT-based fluorescent probes were demonstrated to be powerful tools for detection and imaging, owing to their significant fluorescence enhancement in response to specific targets. While numerous examples of fluorescence-based PeT have been frequently reported, there is not even a single example of a PeT probe that operates via a chemiluminescence mode. Here we report the first PeT-based turn-on probe that acts via a chemiluminescent operation mode. We designed, synthesized, and evaluated a novel chemiluminescent probe, featuring a PeT-based turn-on mechanism. The probe consists of a phenoxy-1,2-dioxetane, linked to an azide unit that acts as a PeT quencher. Upon cycloaddition of a strained cycloalkyne with the azide, a triazole-dioxetane is formed, which undergoes relatively slow chemiexcitation, resulting in a measurement window with an exceptionally high signal-to-noise ratio (over 5000-fold). The PeT-dioxetane probe could effectively detect and image two model proteins labeled with strained cycloalkyne units (Myc-DBCO and Max-DBCO) through either NHS or maleimide conjugations. Comparative analysis shows that our PeT-based chemiluminescent probe significantly outperforms a commercially available fluorescent analog. We anticipate that the insights gained from this study will facilitate the development of additional chemiluminescent probes utilizing various PeT-quenching pathways.
基于 PeT 的荧光探针已被证明是检测和成像的强大工具，因为它们能显著增强对特定目标的荧光反应。虽然基于荧光的 PeT 的例子屡见报端，但通过化学发光模式工作的 PeT 探针却连一个例子都没有。在此，我们报告了首个通过化学发光工作模式工作的基于 PeT 的开启探针。我们设计、合成并评估了一种新型化学发光探针，其特点是基于 PeT 的开启机制。该探针由一个苯氧基-1,2-二氧杂环丁烷和一个叠氮化物单元组成，叠氮化物单元是一种 PeT 淬灭剂。当受约束环烷烃与叠氮化物发生环加成反应时，就会形成三唑-二氧杂环丁烷，其化学激发速度相对较慢，从而产生一个信噪比极高（超过 5000 倍）的测量窗口。PeT 二氧杂环丁烷探针通过 NHS 或马来酰亚胺共轭，可以有效地检测和成像两种用应变环炔单元（Myc-DBCO 和 Max-DBCO）标记的模型蛋白质。对比分析表明，我们基于 PeT 的化学发光探针明显优于市售的荧光类似物。我们预计，从这项研究中获得的启示将有助于开发更多利用各种 PeT 淬灭途径的化学发光探针。
{"title":"Unprecedented Photoinduced-Electron-Transfer Probe with a Turn-ON Chemiluminescence Mode-of-Action","authors":"Doron, Shabat, Maya, David, Sara, Gutkin, Raj V., Nithun, Muhammad, Jbara","doi":"10.26434/chemrxiv-2024-vj8f6","DOIUrl":"https://doi.org/10.26434/chemrxiv-2024-vj8f6","url":null,"abstract":"PeT-based fluorescent probes were demonstrated to be powerful tools for detection and imaging, owing to their significant fluorescence enhancement in response to specific targets. While numerous examples of fluorescence-based PeT have been frequently reported, there is not even a single example of a PeT probe that operates via a chemiluminescence mode. Here we report the first PeT-based turn-on probe that acts via a chemiluminescent operation mode. We designed, synthesized, and evaluated a novel chemiluminescent probe, featuring a PeT-based turn-on mechanism. The probe consists of a phenoxy-1,2-dioxetane, linked to an azide unit that acts as a PeT quencher. Upon cycloaddition of a strained cycloalkyne with the azide, a triazole-dioxetane is formed, which undergoes relatively slow chemiexcitation, resulting in a measurement window with an exceptionally high signal-to-noise ratio (over 5000-fold). The PeT-dioxetane probe could effectively detect and image two model proteins labeled with strained cycloalkyne units (Myc-DBCO and Max-DBCO) through either NHS or maleimide conjugations. Comparative analysis shows that our PeT-based chemiluminescent probe significantly outperforms a commercially available fluorescent analog. We anticipate that the insights gained from this study will facilitate the development of additional chemiluminescent probes utilizing various PeT-quenching pathways.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267136","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 : 2024-09-18DOI: 10.26434/chemrxiv-2024-sslzp-v2
Agastya Prakash, Bhati, Shunzhou, Wan, Peter V., Coveney
Free energy calculations for protein-ligand complexes have become widespread in recent years owing to several conceptual, methodological and technological advances. Central among these is the use of ensemble methods which permits accurate, precise and reproducible predictions and are necessary for uncertainty quantification. Absolute binding free energies (ABFEs) are challenging to predict using alchemical methods and their routine application in drug discovery has remained out of reach until now. Here, we apply ensemble alchemical ABFE methods to a large dataset comprising 219 ligand-protein complexes and obtain statistically robust results with high accuracy (< 1 kcal/mol). We compare equilibrium and non-equilibrium methods for ABFE predictions at large scale and provide a systematic critical assessment of each method. The equilibrium method is more accurate, precise, faster, computationally more cost-effective and requires a much simpler protocol, making it preferable for large scale and blind applications. We find that the calculated free energy distributions are non-normal and discuss the consequences. We recommend a definitive protocol to perform ABFE calculations optimally. Using this protocol, it is possible to perform thousands of ABFE calculations within a few hours on modern exascale machines.
{"title":"Equilibrium and Non-equilibrium Ensemble Methods for Accurate, Precise and Reproducible Absolute Binding Free Energy Calculations","authors":"Agastya Prakash, Bhati, Shunzhou, Wan, Peter V., Coveney","doi":"10.26434/chemrxiv-2024-sslzp-v2","DOIUrl":"https://doi.org/10.26434/chemrxiv-2024-sslzp-v2","url":null,"abstract":"Free energy calculations for protein-ligand complexes have become widespread in recent years owing to several conceptual, methodological and technological advances. Central among these is the use of ensemble methods which permits accurate, precise and reproducible predictions and are necessary for uncertainty quantification. Absolute binding free energies (ABFEs) are challenging to predict using alchemical methods and their routine application in drug discovery has remained out of reach until now. Here, we apply ensemble alchemical ABFE methods to a large dataset comprising 219 ligand-protein complexes and obtain statistically robust results with high accuracy (< 1 kcal/mol). We compare equilibrium and non-equilibrium methods for ABFE predictions at large scale and provide a systematic critical assessment of each method. The equilibrium method is more accurate, precise, faster, computationally more cost-effective and requires a much simpler protocol, making it preferable for large scale and blind applications. We find that the calculated free energy distributions are non-normal and discuss the consequences. We recommend a definitive protocol to perform ABFE calculations optimally. Using this protocol, it is possible to perform thousands of ABFE calculations within a few hours on modern exascale machines.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267138","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 : 2024-09-18DOI: 10.26434/chemrxiv-2024-9kfl4
John, Proudfoot
A model, based on receptor occupancy theory, for signaling due to receptor A and co-receptor B colocalization in the presence of a stable cell-cell interface reveals that a non-selective antagonist of receptor A with affinity for a receptor C on the trans-cell can induce as well as inhibit the signal due to A. As a result, assertion of selectivity for agents acting in such a system should be supported by measurement of signal when the co-receptor B is absent. For conditions where the co-receptor B is non-functional, the model reveals the potential to rescue function through bifunctional ligands, such as bispecific antibodies, antibody conjugates or even bifunctional tethered small molecules.
根据受体占位理论建立的受体 A 和共受体 B 共定位在稳定的细胞-细胞界面上产生信号的模型显示，对跨细胞上的受体 C 具有亲和力的受体 A 非选择性拮抗剂既能诱导也能抑制 A 产生的信号。对于共受体 B 无功能的情况，该模型揭示了通过双功能配体（如双特异性抗体、抗体共轭物或甚至双功能系链小分子）挽救功能的潜力。
{"title":"Non-selective antagonists acting at a stable cell-cell interface have the potential to induce signaling","authors":"John, Proudfoot","doi":"10.26434/chemrxiv-2024-9kfl4","DOIUrl":"https://doi.org/10.26434/chemrxiv-2024-9kfl4","url":null,"abstract":"A model, based on receptor occupancy theory, for signaling due to receptor A and co-receptor B colocalization in the presence of a stable cell-cell interface reveals that a non-selective antagonist of receptor A with affinity for a receptor C on the trans-cell can induce as well as inhibit the signal due to A. As a result, assertion of selectivity for agents acting in such a system should be supported by measurement of signal when the co-receptor B is absent. For conditions where the co-receptor B is non-functional, the model reveals the potential to rescue function through bifunctional ligands, such as bispecific antibodies, antibody conjugates or even bifunctional tethered small molecules.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267143","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}
Tremendous efforts have been made to directly identify serum components using traditional omics approaches. However, several unmet medical needs persist, particularly for chronic diseases that lack reliable biomarkers. The subtle physicochemical abnormality of serum has been widely overlooked and currently lacks detection methods. Inspired by the bat echolocation mechanism, we proposed a chemiluminescence “echoes” approach to depict the disease-specific signatures in biofluids. Specifically, Alzheimer’s disease (AD) serums were used for proof-of-concept study. We first demonstrated the discrepancy in physicochemical properties between AD and healthy control (HC) serums. On this basis, we developed a simple, fast and versatile UNICODE (UNiversal Interaction of Chemiluminescence echOes for Disease Evaluation) array for AD diagnosis. By employing a "bat" probe (ADLumin-1), which generates chemiluminescence autonomously, and combined with a panel of “flag” molecules that enable “echo” formation, we were able to create distinct signatures for various serum components and subtle physicochemical environments. To develop an AD-specific UNICODE diagnosis, we screened a library of over 1000 small molecules, and identified 12 “flag” molecules (top-12) that optimally depict the differences between AD and HC serums. Finally, we used the top-12 array for AD diagnosis. By modeling the UNICODE signatures with seven machine learning methods, we successfully differentiated AD (n = 31) and HC (n = 37) serums, and our best model of random forest provided accuracy = 85.48%, precision = 85.00%, recall = 88.60%, f1 = 85.63%, and AUC = 90.24%. Our strategy could provide new insights into biofluid abnormality and prototype tools for developing liquid biopsy diagnoses for AD and other diseases.
在利用传统的全息方法直接鉴定血清成分方面，人们已经做出了巨大的努力。然而，一些尚未满足的医疗需求依然存在，尤其是缺乏可靠生物标志物的慢性疾病。血清中微妙的物理化学异常一直被广泛忽视，目前也缺乏检测方法。受蝙蝠回声定位机制的启发，我们提出了一种化学发光 "回声 "方法来描述生物液体中的疾病特异性特征。具体来说，我们使用阿尔茨海默病（AD）血清进行概念验证研究。我们首先证明了阿尔茨海默病（AD）血清与健康对照（HC）血清在理化性质上的差异。在此基础上，我们开发了一种用于诊断 AD 的简单、快速和多功能的 UNICODE（用于疾病评估的化学发光回声通用相互作用）阵列。通过使用能自主产生化学发光的 "蝙蝠 "探针（ADLumin-1），并结合能形成 "回声 "的 "标志 "分子，我们能够为各种血清成分和微妙的理化环境创建独特的特征。为了开发出针对 AD 的 UNICODE 诊断方法，我们筛选了一个包含 1000 多种小分子的库，并确定了 12 个 "标志 "分子（top-12），它们能最佳地描述 AD 血清和 HC 血清之间的差异。最后，我们将前 12 个分子阵列用于 AD 诊断。通过使用七种机器学习方法对UNICODE特征建模，我们成功地区分了AD（n = 31）和HC（n = 37）血清，最佳随机森林模型的准确率为85.48%，精确率为85.00%，召回率为88.60%，f1 = 85.63%，AUC = 90.24%。我们的策略可以为生物流体异常提供新的见解，并为开发针对AD和其他疾病的液体活检诊断原型工具提供新的思路。
{"title":"Chemiluminescence signature arrays coupling with machine learning for Alzheimer’s disease serum diagnosis","authors":"Chongzhao, Ran, Biyue, Zhu, Yanbo, Li, Jing, Zhang, Jun, Yang, Shi, Kuang, Johnson, Wang, Shiqian, Shen, Xuan, Zhai, Jiajun, Xie, Astra, Yu","doi":"10.26434/chemrxiv-2024-vs1m9","DOIUrl":"https://doi.org/10.26434/chemrxiv-2024-vs1m9","url":null,"abstract":"Tremendous efforts have been made to directly identify serum components using traditional omics approaches. However, several unmet medical needs persist, particularly for chronic diseases that lack reliable biomarkers. The subtle physicochemical abnormality of serum has been widely overlooked and currently lacks detection methods. Inspired by the bat echolocation mechanism, we proposed a chemiluminescence “echoes” approach to depict the disease-specific signatures in biofluids. Specifically, Alzheimer’s disease (AD) serums were used for proof-of-concept study. We first demonstrated the discrepancy in physicochemical properties between AD and healthy control (HC) serums. On this basis, we developed a simple, fast and versatile UNICODE (UNiversal Interaction of Chemiluminescence echOes for Disease Evaluation) array for AD diagnosis. By employing a \"bat\" probe (ADLumin-1), which generates chemiluminescence autonomously, and combined with a panel of “flag” molecules that enable “echo” formation, we were able to create distinct signatures for various serum components and subtle physicochemical environments. To develop an AD-specific UNICODE diagnosis, we screened a library of over 1000 small molecules, and identified 12 “flag” molecules (top-12) that optimally depict the differences between AD and HC serums. Finally, we used the top-12 array for AD diagnosis. By modeling the UNICODE signatures with seven machine learning methods, we successfully differentiated AD (n = 31) and HC (n = 37) serums, and our best model of random forest provided accuracy = 85.48%, precision = 85.00%, recall = 88.60%, f1 = 85.63%, and AUC = 90.24%. Our strategy could provide new insights into biofluid abnormality and prototype tools for developing liquid biopsy diagnoses for AD and other diseases.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142269839","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 : 2024-09-18DOI: 10.26434/chemrxiv-2024-qr6kv
Dhiman, Ray
Studying the kinetics of long-timescale rare events is a fundamental challenge in molecular simulation. To address this problem, we propose an integration of two different rare-event sampling philosophies: biased enhanced sampling and unbiased path sampling. Enhanced sampling methods e.g. metadynamics can facilitate enthalpic barrier crossing by applying an external bias potential. On the contrary, path sampling methods like weighted ensemble (WE) lack explicit mechanisms to overcome energetic barriers. However, they can accelerate the exploration of rugged free energy surfaces through trajectory resampling. We show that a judicious combination of the weighted ensemble with a metadynamics-like algorithm, can synergize the strengths and mitigate the deficiencies of path sampling and enhanced sampling approaches. The resulting integrated sampling (IS) algorithm improves the computational efficiency of calculating the kinetics of peptide conformational transitions, protein unfolding, and the dissociation of a ligand-receptor complex. Furthermore, the IS approach can direct sampling along the minimum free energy pathway even when the collective variable used for biasing is suboptimal. These advantages make the integrated sampling algorithm suitable for studying the kinetics of complex molecular systems of biological and pharmaceutical relevance.
{"title":"Integrating Path Sampling with Enhanced Sampling for Rare-event Kinetics","authors":"Dhiman, Ray","doi":"10.26434/chemrxiv-2024-qr6kv","DOIUrl":"https://doi.org/10.26434/chemrxiv-2024-qr6kv","url":null,"abstract":"Studying the kinetics of long-timescale rare events is a fundamental challenge in molecular simulation. To address this problem, we propose an integration of two different rare-event sampling philosophies: biased enhanced sampling and unbiased path sampling. Enhanced sampling methods e.g. metadynamics can facilitate enthalpic barrier crossing by applying an external bias potential. On the contrary, path sampling methods like weighted ensemble (WE) lack explicit mechanisms to overcome energetic barriers. However, they can accelerate the exploration of rugged free energy surfaces through trajectory resampling. We show that a judicious combination of the weighted ensemble with a metadynamics-like algorithm, can synergize the strengths and mitigate the deficiencies of path sampling and enhanced sampling approaches. The resulting integrated sampling (IS) algorithm improves the computational efficiency of calculating the kinetics of peptide conformational transitions, protein unfolding, and the dissociation of a ligand-receptor complex. Furthermore, the IS approach can direct sampling along the minimum free energy pathway even when the collective variable used for biasing is suboptimal. These advantages make the integrated sampling algorithm suitable for studying the kinetics of complex molecular systems of biological and pharmaceutical relevance.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267141","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 : 2024-09-18DOI: 10.26434/chemrxiv-2024-jg6bn
Vivian S., Lin, Aaron T., Wright, Stephen J., Callister, Leo J., Gorham, Gerard X., Lomas, Agne, Sveistyte, John T., Melchior, Priscila M., Lalli, Chathuri J., Kombala, Tong, Zhang, Vanessa L., Paurus
Activity-based protein profiling (ABPP) is a chemoproteomic technique that uses chemical probes to label active enzymes selectively and covalently in complex proteomes. Competitive ABPP, which involves treatment of the active proteome with an analyte of interest, is especially powerful for profiling how small molecules impact specific protein activities. Advances in higher throughput workflows have made it possible to generate extensive competitive ABPP data across various biological systems and treatments, making this approach highly appealing for characterizing shared and unique proteins affected by perturbations such as drug or chemical exposures. To use the competitive ABPP approach effectively to understand potential adverse effects of chemicals of concern, a wide range of concentrations may be needed, particularly for chemicals that may lack toxicity data. In this work, we present an integral competitive ABPP method that enables target sensitivity differentiation across a wide range of concentrations for the model organophosphate (OP), paraoxon. Using previously developed OP-ABPs, we optimized conditions for tandem mass tag (TMT) multiplexing of ABPP samples and compared conventional competitive ABPP involving discrete samples at various paraoxon concentrations with pooling of samples across that same concentration range. The results show that small vs. large differences in integral intensities for the competitive sample can be used to distinguish low vs. high sensitivity proteins, respectively, without increasing the overall number of samples. We envision the integral ABPP method will provides a means to screen diverse chemicals more rapidly to identify both highly sensitive and less sensitive protein targets.
{"title":"An integral activity-based protein profiling (IABPP) method for higher throughput determination of protein target sensitivity to small molecules","authors":"Vivian S., Lin, Aaron T., Wright, Stephen J., Callister, Leo J., Gorham, Gerard X., Lomas, Agne, Sveistyte, John T., Melchior, Priscila M., Lalli, Chathuri J., Kombala, Tong, Zhang, Vanessa L., Paurus","doi":"10.26434/chemrxiv-2024-jg6bn","DOIUrl":"https://doi.org/10.26434/chemrxiv-2024-jg6bn","url":null,"abstract":"Activity-based protein profiling (ABPP) is a chemoproteomic technique that uses chemical probes to label active enzymes selectively and covalently in complex proteomes. Competitive ABPP, which involves treatment of the active proteome with an analyte of interest, is especially powerful for profiling how small molecules impact specific protein activities. Advances in higher throughput workflows have made it possible to generate extensive competitive ABPP data across various biological systems and treatments, making this approach highly appealing for characterizing shared and unique proteins affected by perturbations such as drug or chemical exposures. To use the competitive ABPP approach effectively to understand potential adverse effects of chemicals of concern, a wide range of concentrations may be needed, particularly for chemicals that may lack toxicity data. In this work, we present an integral competitive ABPP method that enables target sensitivity differentiation across a wide range of concentrations for the model organophosphate (OP), paraoxon. Using previously developed OP-ABPs, we optimized conditions for tandem mass tag (TMT) multiplexing of ABPP samples and compared conventional competitive ABPP involving discrete samples at various paraoxon concentrations with pooling of samples across that same concentration range. The results show that small vs. large differences in integral intensities for the competitive sample can be used to distinguish low vs. high sensitivity proteins, respectively, without increasing the overall number of samples. We envision the integral ABPP method will provides a means to screen diverse chemicals more rapidly to identify both highly sensitive and less sensitive protein targets.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267179","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}
Most traditional optical biosensors operate through molecular recognition, where ligand binding causes conformational changes that lead to optical perturbations in the emitting motif. Optical sensors developed from single-strand DNA functionalized single-walled carbon nanotubes (ssDNA-SWCNT) have started to make useful contributions to biological research. However, the mechanisms underlying their function have remained poorly understood. In this study, we used a combination of experimental and computational approaches to show that ligand binding alone is not sufficient for optical modulation in this class of synthetic biosensors. Instead, the optical response that occurs after ligand binding is highly dependent on the chemical properties of the ligands, resembling mechanisms seen in activity-based biosensors. Specifically, we show that in ssDNA-SWCNT catecholamine sensors, the optical response correlates positively with electron density on the aryl motif, even when ligand binding affinities are similar. These findings could serve as a foundation for tuning the performance of existing sensors and guiding the development of new biosensors of this class.
大多数传统的光学生物传感器都是通过分子识别来工作的，配体结合会引起构象变化，从而导致发射图案的光学扰动。由单链 DNA 功能化单壁碳纳米管（ssDNA-SWCNT）开发的光学传感器已开始为生物研究做出有益的贡献。然而，人们对其功能的基本机制仍然知之甚少。在这项研究中，我们结合使用了实验和计算方法，结果表明在这类合成生物传感器中，仅靠配体结合不足以实现光学调制。相反，配体结合后产生的光学响应高度依赖于配体的化学特性，这与基于活性的生物传感器的机制相似。具体来说，我们发现在 ssDNA-SWCNT 儿茶酚胺传感器中，即使配体的结合亲和力相似，光学响应也与芳基基团上的电子密度呈正相关。这些发现可作为调整现有传感器性能的基础，并指导开发此类新型生物传感器。
{"title":"Molecular Determinants of Optical Modulation in ssDNA-Carbon Nanotube Biosensors: Insights from Experimental and Computational Approaches","authors":"Abraham, Beyene, Andrew, Krasley, Sayantani, Chakraborty, Lela, Vukovic","doi":"10.26434/chemrxiv-2024-8k2q2","DOIUrl":"https://doi.org/10.26434/chemrxiv-2024-8k2q2","url":null,"abstract":"Most traditional optical biosensors operate through molecular recognition, where ligand binding causes conformational changes that lead to optical perturbations in the emitting motif. Optical sensors developed from single-strand DNA functionalized single-walled carbon nanotubes (ssDNA-SWCNT) have started to make useful contributions to biological research. However, the mechanisms underlying their function have remained poorly understood. In this study, we used a combination of experimental and computational approaches to show that ligand binding alone is not sufficient for optical modulation in this class of synthetic biosensors. Instead, the optical response that occurs after ligand binding is highly dependent on the chemical properties of the ligands, resembling mechanisms seen in activity-based biosensors. Specifically, we show that in ssDNA-SWCNT catecholamine sensors, the optical response correlates positively with electron density on the aryl motif, even when ligand binding affinities are similar. These findings could serve as a foundation for tuning the performance of existing sensors and guiding the development of new biosensors of this class.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267149","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}
Water molecules at the solid-liquid interface display intricate behaviours sensitive to small changes. The presence of different interfacial components, such as cations or functional groups, shape the physical and chemical properties of the hydrogen bond network. Understanding such interfacial hydrogen-bond networks is essential for a large range of applications and scientific questions. To probe the interfacial hydrogen-bond network, atmospheric water capture is a powerful tool. Here, we experimentally observe that a calcium ion on a calcium-intercalated graphene oxide aerogel (Ca-GOA) surface captures 3.2 times more water molecules than in its freestanding state. From experimental Van’t Hoff estimation and density functional theory (DFT) calculations, we uncover the synergistically enhanced hydrogen-bond network of the calcium ion-epoxide complex due to significantly larger polarizations and hydrogen bond enthalpies. This study reveals valuable insights into the interfacial water hydrogen-bond network on functionalized carbon-cation complexed surfaces and potential pathways for future atmospheric water generation technologies.
{"title":"Synergetic hydrogen-bond network of functionalized graphene and cations for enhanced atmospheric water capture","authors":"Rakesh, Joshi, Xiaojun, Ren, Xiao, Sui, Llewellyn, Owens, Dali, Ji, Xinyue, Wen, Yuta, Nishina, Kamal , Pant, Vanesa, Quintano, Daria , Andreeva, Kostya, Novoselov, Amir, Karton, Tobias, Foller, Daisuke, Asanoma","doi":"10.26434/chemrxiv-2024-m9f3h-v2","DOIUrl":"https://doi.org/10.26434/chemrxiv-2024-m9f3h-v2","url":null,"abstract":"Water molecules at the solid-liquid interface display intricate behaviours sensitive to small changes. The presence of different interfacial components, such as cations or functional groups, shape the physical and chemical properties of the hydrogen bond network. Understanding such interfacial hydrogen-bond networks is essential for a large range of applications and scientific questions. To probe the interfacial hydrogen-bond network, atmospheric water capture is a powerful tool. Here, we experimentally observe that a calcium ion on a calcium-intercalated graphene oxide aerogel (Ca-GOA) surface captures 3.2 times more water molecules than in its freestanding state. From experimental Van’t Hoff estimation and density functional theory (DFT) calculations, we uncover the synergistically enhanced hydrogen-bond network of the calcium ion-epoxide complex due to significantly larger polarizations and hydrogen bond enthalpies. This study reveals valuable insights into the interfacial water hydrogen-bond network on functionalized carbon-cation complexed surfaces and potential pathways for future atmospheric water generation technologies.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267147","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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