ACS Publications最新文献

{"title":"Biological Regulation Studied <i>in Vitro</i> and <i>in Cellulo</i> with Modified Proteins.","authors":"Shengxi Chen, Larisa M Dedkova, Sidney M Hecht","doi":"10.1021/acs.accounts.5c00023","DOIUrl":"10.1021/acs.accounts.5c00023","url":null,"abstract":"&lt;p&gt;&lt;p&gt;ConspectusProteins and peptides occur ubiquitously in organisms and play key functional roles, as structural elements and catalysts. Their major natural source is ribosomal synthesis, which produces polypeptides from 20 amino acid building blocks. Peptides containing noncanonical amino acids have long been prepared by chemical synthesis, which has provided a wealth of physiologically active compounds. Comparatively, preparing modified proteins has been more challenging. Site-directed mutagenesis provided an important advance but was initially limited to canonical amino acids. New techniques for tRNA activation with noncanonical amino acids subsequently increased the scope of site-directed mutagenesis.Our report in 2012 demonstrated that modification of bacterial ribosomes at key positions enabled the selection of ribosomes capable of introducing β-amino acids into proteins &lt;i&gt;in vitro&lt;/i&gt;. The generality of the selection procedure was tested further. Ribosomes capable of incorporating dipeptides, conformationally constrained dipeptides, dipeptidometics with embedded fluorophores, contiguous nucleobase amino acids, and phosphorylated amino acids were successfully identified.In this Account, we focus on the application of the new technology to dramatically alter protein structure in ways that enable new strategies for understanding and altering protein function. To illustrate the robustness of the technology we have provided examples studied &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in cellulo&lt;/i&gt;. The first category involves the introduction of nucleobase amino acids into proteins in support of specific interactions with RNA and DNA. The energetic differences between potential protein-nucleic acid complexes formed from two binding partners are often quite small. It seems logical to think that selective binding can be achieved by using a nucleobase moiety in each of the binding partners by utilizing known interactions between nucleic acid bases (located in the protein and nucleic acid) to achieve energetically favorable interactions. We do so both &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in cellulo&lt;/i&gt;. A second focus has involved the design of small fluorescent probes not much larger than amino acids that are genetically encodable and which can be incorporated during protein biosynthesis, serving as detectable probes of protein trafficking and interaction with other macromolecules. We provide an &lt;i&gt;in vitro&lt;/i&gt; example of strongly fluorescent tryptophan analogues positioned at single sites within dihydrofolate reductase, permitting selective communication with a FRET acceptor at a known position, even in the presence of several tryptophans. An oxazole amino acid, weakly fluorescent in aqueous solution, fluoresced more strongly following incorporation into MreB, a scaffold protein produced &lt;i&gt;in cellulo&lt;/i&gt;. Finally, we describe the introduction of a single phosphorylated tyrosine into the p50 subunit of NF-κB. When present at either of two key positions, the resulting NF-κB sig","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"1109-1119"},"PeriodicalIF":16.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Directed Evolution of a Macrolide-Sensing Transcription Factor Biosensor for the Detection of Macrolactone Aglycones via \"Effector Walking\" and Efflux Pump Deletion.","authors":"Lindsay C La Fleur, Zhongtian Zhang, Christian McRoberts-Amador, Jayani Christopher, Megan Reed, Jianting Zheng, T Ashton Cropp, Gavin J Williams","doi":"10.1021/acs.biochem.4c00795","DOIUrl":"10.1021/acs.biochem.4c00795","url":null,"abstract":"<p><p>Glycosylated macrolactones (macrolides) often display broad and potent biological activities and are targets for drug development and discovery. The modular genetic organization of macrolide polyketide synthases (PKSs) and various polyketide tailoring enzymes has inspired the combinatorial biosynthesis of new-to-nature macrolides. However, most engineered PKS and macrolide biosynthetic pathways are ineffective and produce reduced or negligible product titers. Directed evolution could improve the activity of engineered PKSs and associated pathways but critically requires a high-throughput screen to identify active variants from large libraries. Transcription factor-based biosensors can be used for this purpose. However, the effector specificity of the only known macrolide-sensing transcription factor MphR is limited to macrolides modified with the sugar, desosamine. The potential applications of MphR are subsequently limited, ruling out the possibility of leveraging MphR to screen libraries of pathway variants that make macrolactones that lack sugars (i.e., macrolide aglycones) such as the direct products of PKSs. In this study, we aimed to engineer the effector specificity of the MphR biosensor strain for detecting macrolide aglycones. By developing an \"effector walking\" strategy coupled with efflux pump deletion, the effector profile of MphR was dramatically broadened to include several erythronolide macrolactones. This work sets the stage for applying directed evolution and other high-throughput screening approaches to various PKSs. Our results suggest a broadly applicable approach to developing biosensors that detect ligands that are very different in structure from the native effector.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":"1560-1571"},"PeriodicalIF":2.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Laryngeal Cancer With Lung Metastases Showing Long-Term Complete Response and Delayed Immune-Related Adverse Event After Nivolumab Discontinuation.","authors":"Takahito Kondo, Munehide Nakatsugawa, Mitsuru Okubo, Hironori Nakamura, Daisuke Yunaiyama, Midori Wakiya, Atsuo Takeda, Naiue Kikawada, Takuma Kishida, Miwako Someya, Shigekazu Yoshida, Yasuo Ogawa, Kiyoaki Tsukahara","doi":"10.1177/01455613211031025","DOIUrl":"10.1177/01455613211031025","url":null,"abstract":"<p><p>We report a case of laryngeal cancer with multiple lung metastases that maintained a complete response (CR) for 18 months after discontinuing nivolumab treatment, with colitis developing 5 months after drug discontinuation. A 65-year-old man was diagnosed with T3N2cM0 stage IVA right supraglottic squamous cell carcinoma that progressed after 1 course of TPF (cisplatin, docetaxel, and 5-fluorouracil) as induction chemotherapy. He underwent total laryngectomy, bilateral neck dissection, pharyngeal reconstruction with anterolateral thigh flap, and creation of a permanent tracheostoma; extranodal extension was detected in the right cervical lymph node metastasis, and the patient underwent adjuvant radiotherapy. Multiple lung metastases occurred during radiotherapy, and the patient was deemed platinum refractory; nivolumab treatment was thus initiated. The tumor proportion score for programmed death-ligand 1-evaluated via antibody testing of the laryngeal tumor-was <1. The patient received 240 mg/body nivolumab every 2 weeks; a computed tomography performed after course 16 of nivolumab treatment confirmed a CR. He exhibited grade 2 thyroid dysfunction, grade 1 interstitial pneumonia, and grade 2 colitis after 6, 7, and 14 months of receiving nivolumab, respectively; treatment was discontinued as despite maintaining a CR, interstitial pneumonia occurred twice. Colitis appeared 5 months after nivolumab discontinuation; nevertheless, a CR was maintained after 18 months.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"222-227"},"PeriodicalIF":16.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39199785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism of Conformational Selection of tRNA^Arg2 by Bacterial Deaminase TadA.","authors":"Jessy Mariam, Sini Porathoor, Ruchi Anand","doi":"10.1021/acs.biochem.4c00649","DOIUrl":"10.1021/acs.biochem.4c00649","url":null,"abstract":"<p><p>Base editing is a common mechanism by which organisms expand their genetic repertoire to access new functions. Here, we explore the mechanism of tRNA recognition in the bacterial deaminase TadA, which exclusively recognizes tRNA^Arg2 and converts the wobble base adenosine (A34) to inosine. We quantitatively evaluate the dynamics of tRNA binding by incorporating the fluorescent adenine analogue 2-aminopurine (2-AP) at position 34 in the wobble base of the anticodon loop. Time-resolved fluorescence and anisotropy studies revealed that the recognition process is finely tuned. Mutations in residues directly involved in facilitating deamination, such as E55A and N42A, showed a minimal impact on binding dynamics. In contrast, mutations in the \"capping residues\", notably R149, unique to prokaryotic TadAs and located 12-15 Å away from the catalytic center, significantly disrupted binding and consequently catalytic activity. The capping residues play a critical role in enabling tRNA recognition, thereby underscoring their importance in enzyme function. Moreover, for effective catalysis, peripheral positively charged residues (R70, R94) that are part of the adjacent subunit in the dimeric assembly are important to splay out the tRNA, assisting in A34 attaining a flipped-out conformation. Perturbations in these extended regions, although 15-20 Å away from the active site, disrupt the binding dynamics and consequently the function, emphasizing the fine regulation of the tRNA recognition process. Analysis reveals that the C-terminal end of the extended helix where R149 is positioned, acts as a selectivity filter imparting exclusivity toward the deamination of tRNA^Arg2 by TadA.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":"1530-1540"},"PeriodicalIF":2.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Charge, Hydrophobicity, and Lipid Type Drive Antimicrobial Peptides' Unique Perturbation Ensembles.","authors":"Kevin J Cheng, Shashank Shastry, Juan David Campolargo, Michael J Hallock, Taras V Pogorelov","doi":"10.1021/acs.biochem.4c00452","DOIUrl":"10.1021/acs.biochem.4c00452","url":null,"abstract":"<p><p>Antimicrobial peptides (AMPs) have emerged as a promising solution to the escalating public health threat caused by multidrug-resistant bacteria. Although ongoing research efforts have established AMP's role in membrane permeabilization and leakage, the precise mechanisms driving these disruption patterns remain unclear. We leverage molecular dynamics (MD) simulations enhanced by membrane mimetic (HMMM) to systematically investigate how the physiochemical properties of magainin (+3) and pexiganan (+9) affect their localization, insertion, curvature perturbation, and membrane binding ensemble. Building on existing microbiology, NMR, circular dichroism, and fluorescence data, our analysis reveals that the lipid makeup is a key determinant in the binding dynamics and structural conformation of AMPs. We find that phospholipid type is crucial for peptide localization, demonstrated through magainin's predominant interaction with lipid tails and pexiganan's with polar headgroups in POPC/POPS membranes. The membrane curvature changes induced by pexiganan relative to magainin suggest that AMPs with larger charges have more potential in modulating bilayer bending. These insights advance our understanding of AMP-membrane interactions at the molecular level, offering guidance for the design of targeted antimicrobial therapies.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":"1484-1500"},"PeriodicalIF":2.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coarse-Grained Simulations of Phosphorylation Regulation of p53 Autoinhibition.","authors":"Shrishti Barethiya, Samantha Schultz, Yumeng Zhang, Jianhan Chen","doi":"10.1021/acs.biochem.4c00668","DOIUrl":"10.1021/acs.biochem.4c00668","url":null,"abstract":"<p><p>Intrinsically disordered proteins (IDPs) are key components of cellular signaling and regulatory networks. They frequently remain dynamic even in complexes and thus rely on potentially subtle shifts in the disordered conformational ensemble for function. Understanding the molecular basis of these fascinating mechanisms of IDP function and regulation requires a detailed characterization of dynamic ensembles in various biologically relevant states. Here, we study the phosphorylation dependence of the dynamic interaction between the N-terminal transactivation domain (NTAD) and DNA-binding domain (DBD) of tumor suppressor p53, which plays a key role in the autoinhibition and regulation of p53 activation or termination during various stages of stress response. By extending the hybrid-resolution (HyRes) coarse-grained (CG) protein force field to model phosphorylated side chains, we show that HyRes simulations accurately recapitulate the effects of phosphorylation on the p53 NTAD/DBD interactions. The simulated ensembles show that phosphorylation of Thr55 as well as Ser46 enhances dynamic NTAD/DBD interactions and further induces conformational shifts that promote trans interactions between two p53 dimers to drive dissociation from DNA. These CG simulations thus provide a strong molecular basis in support of previous experimental studies suggesting the central role of dynamic interactions of disordered domains and phosphorylation in the function of p53. The success of this study also suggests that HyRes provides an efficient and viable tool for studying dynamic interactions and post-translational modifications in IDP function and regulation.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":"1636-1645"},"PeriodicalIF":2.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reimagining Dearomatization: Arenophile-Mediated Single-Atom Insertions and π-Extensions.","authors":"Zohaib Siddiqi, David Sarlah","doi":"10.1021/acs.accounts.5c00035","DOIUrl":"10.1021/acs.accounts.5c00035","url":null,"abstract":"&lt;p&gt;&lt;p&gt;ConspectusDearomatization of simple aromatics serves as one of the most direct strategies for converting abundant chemical feedstocks into three-dimensional value-added products. Among such transformations, cycloadditions between arenes and alkenes have historically offered effective means to construct complex polycyclic architectures. However, traditionally harsh conditions, such as high-energy UV light irradiation, have greatly limited the scope of this transformation. Nevertheless, recent progress has led to the development of visible-light-promoted dearomative photocycloadditions with expanded scope capable of preparing complex bicyclic structures.A fundamentally distinct approach to dearomative photocycloadditions involves the visible-light activation of arenophiles, which undergo &lt;i&gt;para&lt;/i&gt;-photocycloaddition with various aromatic compounds to produce arene-arenophile cycloadducts. While only transiently stable and subject to retro-cycloaddition, further functionalization of the photocycloadducts has allowed for the development of a wide collection of dearomatization methodologies that access products orthogonal to existing chemical and biological processes. Central to this strategy was the observation that arene-arenophile photocycloaddition reveals a π-system that can be functionalized through traditional olefin chemistry. Coupled with subsequent [4 + 2]-cycloreversion of the arenophile, this process acts to effectively isolate a single π-system from an aromatic ring. We have developed several transformations that bias this methodology to perform dearomative single-atom insertion and π-extension reactions to prepare unique products that cannot be prepared easily through traditional means.Through the application of a dearomative epoxidation, we were able to develop a method for the epoxidation of arenes and pyridines to arene-oxides and pyridine-oxides, respectively. Notably, when this arenophile chemistry is applied to polycyclic arenes, photocycloaddition reveals a π-system transposed from the site of native olefinic reactivity, enabling unique site-selectivity for dearomative functionalization. As a result, we were able to perform a single-atom insertion of oxygen into polycyclic (aza)arenes to prepare 3-benzoxepines. When applying this strategy in the context of cyclopropanations, we were able to accomplish a dearomative cyclopropanation of polycyclic (aza)arenes which yield benzocycloheptatrienes upon cycloreversion. Notably, while the Buchner ring expansion is a powerful method for the direct single-atom insertion of carbon into arenes, the corresponding cyclopropanation of polycyclic arenes does not yield ring-expanded products. Furthermore, this strategy could be utilized for the synthesis of novel nanographenes through the development of an M-region annulative π-extension (M-APEX) reaction. Traditionally, methods for π-extension rely on the native reactivity of polycyclic aromatics at the K- and bay-region. However, photocy","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"1134-1150"},"PeriodicalIF":16.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BODIPY-Based Photothermal Agent Incorporating Azulene for Enhanced NIR Absorption and Tumor Ablation.","authors":"Kai Nishimura, Mikiya Kato, Tomoya Fukui, Kazuki Miura, Masato Tsuda, Satoshi Okada, Takanori Fukushima, Hiroyuki Nakamura","doi":"10.1021/acs.molpharmaceut.5c00071","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00071","url":null,"abstract":"<p><p>Photothermal therapy (PTT) is a promising minimally invasive treatment that converts light energy into localized heat for tumor ablation. Indocyanine green (ICG), the only clinically approved photothermal agent (PTA), suffers from rapid photobleaching and poor tumor retention, underscoring the urgent need for next-generation PTAs with improved properties. In this study, we report AzuGlu-BODIPY, a novel azulene-containing BODIPY-based PTA incorporating 1,2,3,4-tetrahydroquinoline and glucose, designed to overcome these limitations. AzuGlu-BODIPY demonstrates a high photothermal conversion efficiency (PCE) of 51%, effective near-infrared (NIR) absorption, and thermal stability in both dimethyl sulfoxide (DMSO) and aqueous solutions. <i>In vitro</i> studies revealed potent photothermal efficacy against cancer cell lines, with IC₅₀ values of 3.1-4.6 μM under 808 nm laser irradiation, while <i>in vivo</i> experiments showed complete tumor regression in 4T1 tumor-bearing mice following localized administration and laser treatment. These results suggest AzuGlu-BODIPY as a promising PTA and provide a versatile platform for advancing azulene-based PTAs with enhanced functionality for PTT.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Binding Motifs of Doubly and Singly Charged Proton-Bound Clusters of B₁₂F₁₂^2- and Diaminoalkanes.","authors":"Arthur E Lee, Patrick Thomas, Courtney Kates, Terrance B McMahon, W Scott Hopkins","doi":"10.1021/acs.jpca.4c08341","DOIUrl":"https://doi.org/10.1021/acs.jpca.4c08341","url":null,"abstract":"<p><p>The complexation of perfluorinated dodecaborate, B₁₂F₁₂^2-, with protonated diaminoalkanes, [H₂N(CH₂)<i>_n</i>H₂N] (<i>n=</i> 2 - 12), is studied with a combination of infrared multiple photon dissociation (IRMPD) action spectroscopy and ion mobility spectrometry. Singly charged clusters of the form [B₁₂F₁₂ + H₂N(CH₂)<i>_n</i>H₂N + H]^- (<i>n =</i> 2-12) and doubly charged clusters of the form [2B₁₂F₁₂ + H₂N(CH₂)<i>_n</i>H₂N + 2H]^2- (<i>n =</i> 2-12) are observed and characterized experimentally and computationally. For the singly charged clusters, low-energy structural motifs associated with monodentate and bidentate binding motifs of the diaminoalkane are computed via a combination of CREST conformer exploration and density functional theory. For the doubly charged clusters, the doubly protonated diaminoalkane acts as a tether between two B₁₂F₁₂^2- cages. Major product channels of the singly charged and doubly charged species are found to be the formation of HB₁₂F₁₂^- via proton transfer and the loss of B₁₂F₁₂^2-. The fragmentation of HB₁₂F₁₂^- leads to several secondary products, including [B₁₂F₁₁ + N₂]^-. Collision cross sections (CCSs) for the singly charged clusters are reported, and the major subpopulation of the gas phase ensemble for the different singly charged species is the bidentate conformation.</p>","PeriodicalId":59,"journal":{"name":"The Journal of Physical Chemistry A","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750287","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":"An Open Source Replication of a Winning Recidivism Prediction Model.","authors":"Giovanni M Circo, Andrew P Wheeler","doi":"10.1177/0306624X221133004","DOIUrl":"10.1177/0306624X221133004","url":null,"abstract":"<p><p>We present results of our winning solution to the National Institute of Justice recidivism forecasting challenge. Our team, \"MCHawks,\" placed highly in both terms of accuracy (as measured via the Brier score), as well as the fairness criteria (weighted by differences in false positive rates between White and Black parolees). We used a non-linear machine learning model, XGBoost, although we detail our search of different model specifications, as many different models' predictive performance is very similar. Our solution to balancing false positive rates is trivial; we bias predictions to always be \"low risk\" so false positive rates for each racial group are zero. We discuss changes to the fairness metric to promote non-trivial solutions. By providing open-source replication materials, it is within the capabilities of others to build just as accurate models without extensive statistical expertise or computational resources.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"438-453"},"PeriodicalIF":16.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40662589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}