Biochemistry Biochemistry最新文献_第2页

Improved Estimates of Folding Stabilities and Kinetics with Multiensemble Markov Models. 利用多集合马尔可夫模型改进折叠稳定性和动力学估算。

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2024-11-19 Epub Date: 2024-11-07 DOI: 10.1021/acs.biochem.4c00573

Si Zhang, Yunhui Ge, Vincent A Voelz

{"title":"Improved Estimates of Folding Stabilities and Kinetics with Multiensemble Markov Models.","authors":"Si Zhang, Yunhui Ge, Vincent A Voelz","doi":"10.1021/acs.biochem.4c00573","DOIUrl":"10.1021/acs.biochem.4c00573","url":null,"abstract":"Markov State Models (MSMs) have been widely applied to understand protein folding mechanisms by predicting long time scale dynamics from ensembles of short molecular simulations. Most MSM estimators enforce detailed balance, assuming that trajectory data are sampled at an equilibrium. This is rarely the case for ab initio folding studies, however, and as a result, MSMs can severely underestimate protein folding stabilities from such data. To remedy this problem, we have developed an enhanced-sampling protocol in which (1) unbiased folding simulations are performed and sparse tICA is used to obtain features that best capture the slowest events in folding, (2) umbrella sampling along this reaction coordinate is performed to observe folding and unfolding transitions, and (3) the thermodynamics and kinetics of folding are estimated using multiensemble Markov models (MEMMs). Using this protocol, folding pathways, rates, and stabilities of a designed α-helical hairpin, Z34C, can be predicted in good agreement with experimental measurements. These results indicate that accurate simulation-based estimates of absolute folding stabilities are within reach, with implications for the computational design of folded miniproteins and peptidomimetics.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":"3045-3056"},"PeriodicalIF":2.9,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602338","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}

引用次数: 0

Probing Aromatic Side Chains Reveals the Site-Specific Melting in the SUMO1 Molten Globule. 探测芳香族侧链可揭示 SUMO1 熔融球中的特定位点熔化。

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2024-11-14 DOI: 10.1021/acs.biochem.4c00366

Simran Arora, Sri Rama Koti Ainavarapu

{"title":"Probing Aromatic Side Chains Reveals the Site-Specific Melting in the SUMO1 Molten Globule.","authors":"Simran Arora, Sri Rama Koti Ainavarapu","doi":"10.1021/acs.biochem.4c00366","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00366","url":null,"abstract":"The conventional idea that a well-defined protein structure governs its functions is being challenged by the evolving significance of conformational flexibility and disorder in influencing protein activity. Here, we focus on the Small Ubiquitin-like MOdifier 1 (SUMO1) protein, a post-translational modifier, which binds various target proteins during the process of SUMOylation. We present evidence supporting the presence of both folded and \"ordered\" molten globule (MG) states in SUMO1 under physiological conditions. We investigate the MG state using a combination of near-UV and far-UV circular dichroism (CD) experiments. Moreover, we dissect the information from the near-UV CD data to gain specific insights about the MG intermediate. This is achieved by mutating specific aromatic amino acids, particularly creating a single-tyrosine mutant S1Y51 (by introducing Y21F and Y91F mutations) and a tryptophan mutant S1F66W. Spectroscopic studies of the mutants as a function of temperature revealed multiple insights. The transition from the folded to the MG state involves a site-specific loss of tertiary packing near Y51 but the region surrounding F66 retained most of its tertiary contacts, suggesting an ordered MG structure. We further demonstrate the increased solvent exposure of Y51 in the MG state by using time-resolved fluorescence and steady-state quenching experiments. The observed conformational flexibility and solvent accessibility, particularly around Y51 that is known to be involved in binding the cognate ligands such as PIASX and its peptide analogues, have biological and functional implications in mediating protein-protein interactions during the SUMOylation process.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612588","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}

引用次数: 0

Dementia risk scores in diverse populations 不同人群的痴呆症风险评分

IF 38.1 3区生物学

Biochemistry Biochemistry Pub Date : 2024-11-13 DOI: 10.1038/s41582-024-01039-6

Lisa Kiani

引用次数: 0

A GSDMD agonist boosts specific antitumor immunity 一种 GSDMD 激动剂能增强特异性抗肿瘤免疫力

IF 44.1 3区生物学

Biochemistry Biochemistry Pub Date : 2024-11-13 DOI: 10.1038/s41422-024-01051-x

Yingying Zhang, Jiahuai Han

引用次数: 0

Oligodendrocyte progenitor cell transplant for MS 少突胶质祖细胞移植治疗多发性硬化症

IF 38.1 3区生物学

Biochemistry Biochemistry Pub Date : 2024-11-13 DOI: 10.1038/s41582-024-01038-7

Lisa Kiani

引用次数: 0

High prevalence of hepatitis B in NMOSD 非传染性疾病中乙型肝炎的高发病率

IF 38.1 3区生物学

Biochemistry Biochemistry Pub Date : 2024-11-13 DOI: 10.1038/s41582-024-01037-8

Lisa Kiani

引用次数: 0

Glymphatic dysfunction in PD clinical progression 淋巴功能障碍与帕金森病临床进展的关系

IF 38.1 3区生物学

Biochemistry Biochemistry Pub Date : 2024-11-13 DOI: 10.1038/s41582-024-01040-z

Lisa Kiani

引用次数: 0

Immune responses influence sex differences in Alzheimer disease 免疫反应影响阿尔茨海默病的性别差异

IF 38.1 3区生物学

Biochemistry Biochemistry Pub Date : 2024-11-13 DOI: 10.1038/s41582-024-01044-9

Ian Fyfe

引用次数: 0

Identification of a Hidden, Highly Aggregation-Prone Intermediate of Full-Length TDP-43 That Triggers its Misfolding and Amyloid Aggregation. 鉴定全长 TDP-43 的一个隐藏的、高度易聚集的中间体，它能触发 TDP-43 的错误折叠和淀粉样蛋白聚集。

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2024-11-12 DOI: 10.1021/acs.biochem.4c00389

Abhilasha A Doke, Santosh Kumar Jha

{"title":"Identification of a Hidden, Highly Aggregation-Prone Intermediate of Full-Length TDP-43 That Triggers its Misfolding and Amyloid Aggregation.","authors":"Abhilasha A Doke, Santosh Kumar Jha","doi":"10.1021/acs.biochem.4c00389","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00389","url":null,"abstract":"In cells, TDP-43 is a crucial protein that can form harmful amyloid aggregates linked to fatal and incurable human neurodegenerative disorders. Normally, TDP-43 exists in a smaller soluble native state that prevents aggregation. However, aging and stress can destabilize this native state, leading to the formation of disease-causing amyloid aggregates via the formation of partially unfolded, high-energy intermediates with a greater tendency to aggregate. These intermediates are crucial in the early stages of amyloid formation and are challenging to study due to their low stability. Understanding the structure of these early aggregation-prone states of TDP-43 is essential for designing effective treatments for TDP-43 proteinopathies. Targeting these initial intermediates could be more effective than focusing on fully formed amyloid aggregates. By disrupting the aggregation process at this early stage, we may be able to prevent the progression of diseases related to TDP-43 aggregation. Hence, we decided to uncover the hidden, high-energy intermediates in equilibrium with the native states of TDP-43 by modulating the thermodynamic stability of the soluble native dimer (N form) and monomeric molten globular state (MG form) of full-length TDP-43. The thermodynamic modulation performed in the current study successfully revealed the highly aggregation-prone intermediate of full-length TDP-43, i.e., PUF. Moreover, we observed that along with high aggregation propensity, the aggregation kinetics and mechanisms of PUF differ from previously identified intermediates of full-length TDP-43 (the MG and I forms). The information regarding the initial aggregation-prone state of full-length TDP-43 could lead to therapies for amyloid diseases by halting early protein aggregation.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612587","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}

引用次数: 0

Structure and Function of Sabinene Synthase, a Monoterpene Cyclase That Generates a Highly Strained [3.1.0] Bicyclic Product. 桧烯合成酶的结构和功能--一种产生高强度 [3.1.0] 双环产物的单萜环化酶。

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2024-11-11 DOI: 10.1021/acs.biochem.4c00476

Matthew N Gaynes, Kristin R Osika, David W Christianson

{"title":"Structure and Function of Sabinene Synthase, a Monoterpene Cyclase That Generates a Highly Strained [3.1.0] Bicyclic Product.","authors":"Matthew N Gaynes, Kristin R Osika, David W Christianson","doi":"10.1021/acs.biochem.4c00476","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00476","url":null,"abstract":"Sabinene is a plant natural product with a distinctive strained [3.1.0] bicyclic ring system that is used commercially as a spicy and pine-like fragrance with citrus undertones. This unusual monoterpene has also been studied as an antifungal and anti-inflammatory agent as well as a next-generation biofuel. In order to understand the molecular determinants of [3.1.0] bicyclic ring formation in sabinene biosynthesis, we now report three X-ray crystal structures of sabinene synthase from Western red cedar, Thuja plicata (TpSS), with open and partially closed active site conformations at 2.21-2.72 Å resolution. We additionally report the complete biochemical characterization of sabinene synthase, including steady-state kinetics, active site mutagenesis, and product array profiling. The catalytic metal ion requirement is unexpectedly broad for a class I terpene cyclase: optimal catalytic activity was measured using Mn2+ or Co2+, with more modest activity observed using Mg2+ or Ni2+. Kinetic parameters were determined for both full-length TpSS and a deletion variant lacking the putative N-terminal plastidial targeting sequence, designated ΔTpSS. Monoterpene product profiles for both indicated similar product arrays independent of the catalytic metal ion used, with sabinene comprising nearly 90% of the total products generated. Site-directed mutagenesis was utilized to probe the function of active site residues, and several mutants yielded altered product arrays. Most notably, the G458A substitution converted ΔTpSS into a high-activity α-pinene synthase. α-Pinene contains a bicyclic [3.1.1] ring system; structural and mechanistic analyses suggest a molecular rationale for the reprogrammed transannulation reaction, leading to the alternative bicyclic product.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612589","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}

引用次数: 0