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[PMID]: 29355525 [Au] Autor: Kim JL; Ha GH; Campo L; Breuer EK [Ad] Endereço: Department of Radiation Oncology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, 60153, USA. [Ti] Título: Negative regulation of BRCA1 by transforming acidic coiled-coil protein 3 (TACC3). [So] Source: Biochem Biophys Res Commun;496(2):633-640, 2018 02 05. [Is] ISSN: 1090-2104 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: In spite of the push to identify modifiers of BRCAness, it still remains unclear how tumor suppressor BRCA1 is lost in breast cancers in the absence of genetic or epigenetic aberrations. Mounting evidence indicates that the transforming acidic coiled-coil 3 (TACC3) plays an important role in the centrosome-microtubule network during mitosis and gene expression, and that deregulation of TACC3 is associated with breast cancer. However, the molecular mechanisms by which TACC3 contributes to breast cancer development have yet to be elucidated. Herein, we found that high levels of TACC3 in human mammary epithelial cells can cause genomic instability possibly in part through destabilizing BRCA1. We also found that high levels of TACC3 inhibited the interaction between BRCA1 and BARD1, thus subsequently allowing the BARD1-uncoupled BRCA1 to be destabilized by ubiquitin-mediated proteosomal pathway. Moreover, there is an inverse correlation between TACC3 and BRCA1 expression in breast cancer tissues. Overall, our findings provide a new insight into the role of TACC3 in genomic instability and breast tumorigenesis. [Mh] Termos MeSH primário: Proteína BRCA1/metabolismo Proteínas Associadas aos Microtúbulos/metabolismo [Mh] Termos MeSH secundário: Neoplasias da Mama/genética Neoplasias da Mama/metabolismo Linhagem Celular Feminino Instabilidade Genômica Seres Humanos Mapas de Interação de Proteínas Estabilidade Proteica Proteólise Proteínas Supressoras de Tumor/metabolismo Ubiquitina-Proteína Ligases/metabolismo Ubiquitinação [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (BRCA1 Protein); 0 (Microtubule-Associated Proteins); 0 (TACC3 protein, human); 0 (Tumor Suppressor Proteins); EC 2.3.2.27 (BARD1 protein, human); EC 2.3.2.27 (Ubiquitin-Protein Ligases) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180309 [Lr] Data última revisão: 180309 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180123 [St] Status: MEDLINE

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[PMID]: 29330050 [Au] Autor: Tanabe A; Nakano K; Nakakido M; Nagatoishi S; Tanaka Y; Tsumoto K; Uchimaru K; Watanabe T [Ad] Endereço: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. [Ti] Título: Production and characterization of a novel site-specific-modifiable anti-OX40-receptor single-chain variable fragment for targeted drug delivery. [So] Source: Biochem Biophys Res Commun;496(2):614-620, 2018 02 05. [Is] ISSN: 1090-2104 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: OX40 receptor (tumor necrosis factor receptor superfamily, member 4; CD134) is a T-cell co-stimulatory molecule that plays an important role in T-cell activation and survival. OX40 receptor is activated by its ligand, OX40L; and modulation of the OX40-OX40L interaction is a promising target for the treatment of autoimmune diseases and cancers. Here, we generated a high-affinity anti-OX40 single-chain variable fragment carrying a C-terminal cysteine residue (scFvC). Physicochemical and functional analyses revealed that the scFvC bound to OX40-expressing cells and was internalized via OX40-mediated endocytosis without inducing phosphorylation of IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha), an important complex in the classical NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathway. In addition, mutation of the 36th cysteine residue in variable region of light chain enabled site-specific chemical modification to carboxy terminal cysteine and improved the thermal stability of the scFvC. These results suggest that this novel high-affinity anti-OX40 scFvC may be useful as a transporter for targeted delivery of small compounds, proteins, peptides, liposomes, and nanoparticles, into OX40-expressing cells for the treatment of autoimmune diseases and cancers. [Mh] Termos MeSH primário: Imunoconjugados/imunologia Receptores OX40/imunologia Anticorpos de Cadeia Única/imunologia [Mh] Termos MeSH secundário: Linhagem Celular Sistemas de Liberação de Medicamentos Escherichia coli/genética Expressão Gênica Seres Humanos Imunoconjugados/química Imunoconjugados/genética Células Jurkat Modelos Moleculares Mutação Puntual Estabilidade Proteica Anticorpos de Cadeia Única/química Anticorpos de Cadeia Única/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Immunoconjugates); 0 (Receptors, OX40); 0 (Single-Chain Antibodies) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180309 [Lr] Data última revisão: 180309 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180114 [St] Status: MEDLINE

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[PMID]: 28465175 [Au] Autor: Malik A; Albogami S; Alsenaidy AM; Aldbass AM; Alsenaidy MA; Khan ST [Ad] Endereço: Department of Biochemistry. Protein Research Chair. College of Science. King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia. Electronic address: amalik@ksu.edu.sa. [Ti] Título: Spectral and thermal properties of novel eye lens ζ-crystallin. [So] Source: Int J Biol Macromol;102:1052-1058, 2017 Sep. [Is] ISSN: 1879-0003 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Eye lenses are exposed to thermal, solar radiations, dryness that enhances cataractogenesis. Some animal lenses contain novel proteins in bulk quantities. ζ-crystallin occurred in three ecologically divergent species, but it's physiological role not known. The truncated variant of ζ-crystallin causes hereditary cataract. Guinea pig ζ-crystallin is temperature-sensitive and rapidly aggregates at 41°C. Camels adopted to survive above 50°C, which raises an interesting question about how it retains lens proteins in the soluble state? Here, we have optimized expression and purification of recombinant camel ζ-crystallin. We have studied thermodynamic and spectroscopic properties using orthogonal techniques. Dynamic multimode spectroscopy results showed that camel ζ-crystallin unfolds via single transition with T value of 60.8±0.1°C and van't Hoff enthalpy of 714.7±7.1kJ/mol. Thermal-shift assay calculates T value of 62°C at pH 7. Additionally, the conformational stability of ζ-crystallin increases with ionic-strength. The influence of pH on ζ-crystallin was evaluated where the protein was found to be stable in the pH range of 6-9, but its stability drastically decreases below pH 6. Our results also showed that quaternary structure of ζ-crystallin drastically changed as a result of lowering pH. This study provides significant understandings onto the conformational, thermodynamic and unfolding pathway of camel ζ-crystallin. [Mh] Termos MeSH primário: Cristalino/química Temperatura Ambiente zeta-Cristalinas/química [Mh] Termos MeSH secundário: Concentração de Íons de Hidrogênio Estabilidade Proteica Desdobramento de Proteína Análise Espectral [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (zeta-Crystallins) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180309 [Lr] Data última revisão: 180309 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170504 [St] Status: MEDLINE

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[PMID]: 28455257 [Au] Autor: Narang SS; Shuaib S; Goyal B [Ad] Endereço: Department of Chemistry, School of Basic and Applied Sciences, Sri Guru Granth Sahib World University, Fatehgarh Sahib 140406, Punjab, India. [Ti] Título: Molecular insights into the inhibitory mechanism of rifamycin SV against ß -microglobulin aggregation: A molecular dynamics simulation study. [So] Source: Int J Biol Macromol;102:1025-1034, 2017 Sep. [Is] ISSN: 1879-0003 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Dialysis-related amyloidosis (DRA) is a severe condition characterized by the accumulation of amyloidogenic ß -microglobulin (ß m) protein around skeletal joints and bones. The small molecules that modulate ß m aggregation have been identified in vitro, however, the underlying inhibitory mechanism remain elusive. In the present study, molecular docking and molecular dynamics (MD) simulations were performed to elucidate the inhibitory mechanism of an antibiotic, rifamycin SV (C ) reported for its in vitro anti-aggregation activity against ß m. The molecular docking analysis highlight that C display hydrophobic contacts with residues in the aggregation prone region of ß m. MD simulations reveal enhanced structural stability of ß m in the presence of C . C inhibit the conformational transition of the C-terminal region of ß m from a ß-sheet to random coil conformation, which is reported for the initiation of fibrillogenesis of ß m. The results of the present study provide insight into the key interactions and underlying inhibitory mechanism of a small molecule against ß m aggregation that will help in the design and development of more potent, novel inhibitors of ß m aggregation. [Mh] Termos MeSH primário: Simulação de Dinâmica Molecular Agregados Proteicos/efeitos dos fármacos Rifamicinas/farmacologia Microglobulina-2 beta/química [Mh] Termos MeSH secundário: Conformação Proteica em Folha beta Estabilidade Proteica Termodinâmica [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Protein Aggregates); 0 (Rifamycins); 0 (beta 2-Microglobulin); DU69T8ZZPA (rifamycin SV) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180309 [Lr] Data última revisão: 180309 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170430 [St] Status: MEDLINE

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[PMID]: 28449057 [Au] Autor: Schumacher MA; Zeng W; Findlay KC; Buttner MJ; Brennan RG; Tschowri N [Ad] Endereço: Department of Biochemistry, Duke University School of Medicine, Durham, NC 27701, USA. [Ti] Título: The Streptomyces master regulator BldD binds c-di-GMP sequentially to create a functional BldD2-(c-di-GMP)4 complex. [So] Source: Nucleic Acids Res;45(11):6923-6933, 2017 Jun 20. [Is] ISSN: 1362-4962 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Streptomyces are ubiquitous soil bacteria that undergo a complex developmental transition coinciding with their production of antibiotics. This transition is controlled by binding of a novel tetrameric form of the second messenger, 3΄-5΄ cyclic diguanylic acid (c-di-GMP) to the master repressor, BldD. In all domains of life, nucleotide-based second messengers allow a rapid integration of external and internal signals into regulatory pathways that control cellular responses to changing conditions. c-di-GMP can assume alternative oligomeric states to effect different functions, binding to effector proteins as monomers, intercalated dimers or, uniquely in the case of BldD, as a tetramer. However, at physiological concentrations c-di-GMP is a monomer and little is known about how higher oligomeric complexes assemble on effector proteins and if intermediates in assembly pathways have regulatory significance. Here, we show that c-di-GMP binds BldD using an ordered, sequential mechanism and that BldD function necessitates the assembly of the BldD2-(c-di-GMP)4 complex. [Mh] Termos MeSH primário: Proteínas de Bactérias/química GMP Cíclico/análogos & derivados Proteínas Repressoras/química Streptomyces [Mh] Termos MeSH secundário: Sítios de Ligação Cristalografia por Raios X GMP Cíclico/química Ligações de Hidrogênio Modelos Moleculares Ligação Proteica Domínios Proteicos Estabilidade Proteica Estrutura Quaternária de Proteína [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Bacterial Proteins); 0 (Repressor Proteins); 61093-23-0 (bis(3',5')-cyclic diguanylic acid); H2D2X058MU (Cyclic GMP) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 180307 [Lr] Data última revisão: 180307 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170428 [St] Status: MEDLINE [do] DOI: 10.1093/nar/gkx287

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[PMID]: 28460458 [Au] Autor: Fang Y; Wang J; Wang G; Zhou C; Wang P; Zhao S; Zhao S; Huang S; Su W; Jiang P; Chang A; Xiang R; Sun P [Ad] Endereço: Department of Immunology, School of Medicine, Nankai University, Tianjin, China. [Ti] Título: Inactivation of p38 MAPK contributes to stem cell-like properties of non-small cell lung cancer. [So] Source: Oncotarget;8(16):26702-26717, 2017 Apr 18. [Is] ISSN: 1949-2553 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Cancer stem cells (CSCs) are recognized as the major source for cancer initiation and recurrence. Yet, the mechanism by which the cancer stem cell properties are acquired and maintained in a cancer cell population is not well understood. In the current study, we observed that the level of active p38 MAPK is downregulated, while the level of the stemness marker SOX2 is upregulated in lung cancer tissues as compared to normal tissues. We further demonstrated that inactivation of p38 is a potential mechanism contributing to acquisition and maintenance of cancer stem cell properties in non-small cell lung cancer (NSCLC) cells. p38, in particular the p38γ and p38δ isoforms, suppresses the cancer stem cell properties and tumor initiating ability of NSCLC cells by promoting the ubiquitylation and degradation of stemness proteins such as SOX2, Oct4, Nanog, Klf4 and c-Myc, through MK2-mediated phosphorylation of Hsp27 that is an essential component of the proteasomal degradation machinery. In contrast, inactivation of p38 in lung cancer cells leads to upregulation of the stemness proteins, thus promoting the cancer stem cell properties of these cells. These findings have demonstrated a novel mechanism by which cancer stem cell properties are acquired and maintained in a cancer cell population, and have revealed a new function of the p38 pathway in suppressing cancer development. These studies have also identified a new pathway that can potentially serve as a target for cancer therapies aimed at eliminating CSCs. [Mh] Termos MeSH primário: Carcinoma Pulmonar de Células não Pequenas/metabolismo Neoplasias Pulmonares/metabolismo Células-Tronco Neoplásicas/metabolismo Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo [Mh] Termos MeSH secundário: Animais Biomarcadores Carcinoma Pulmonar de Células não Pequenas/genética Linhagem Celular Tumoral Transformação Celular Neoplásica/genética Transformação Celular Neoplásica/metabolismo Modelos Animais de Doenças Ativação Enzimática Regulação Neoplásica da Expressão Gênica Xenoenxertos Seres Humanos Neoplasias Pulmonares/genética Masculino Camundongos Fosforilação Complexo de Endopeptidases do Proteassoma/metabolismo Estabilidade Proteica Proteólise Fatores de Transcrição SOXB1/genética Fatores de Transcrição SOXB1/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Biomarkers); 0 (SOX2 protein, human); 0 (SOXB1 Transcription Factors); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases); EC 3.4.25.1 (Proteasome Endopeptidase Complex) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180305 [Lr] Data última revisão: 180305 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170503 [St] Status: MEDLINE [do] DOI: 10.18632/oncotarget.15804

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[PMID]: 28744580 [Au] Autor: Wester A; Devocelle M; Tallant EA; Chappell MC; Gallagher PE; Paradisi F [Ad] Endereço: School of Chemistry, University College Dublin, Dublin, Ireland. [Ti] Título: Stabilization of Angiotensin-(1-7) by key substitution with a cyclic non-natural amino acid. [So] Source: Amino Acids;49(10):1733-1742, 2017 10. [Is] ISSN: 1438-2199 [Cp] País de publicação: Austria [La] Idioma: eng [Ab] Resumo: Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide hormone of the renin-angiotensin-aldosterone system, is a promising candidate as a treatment for cancer that reflects its anti-proliferative and anti-angiogenic properties. However, the peptide's therapeutic potential is limited by the short half-life and low bioavailability resulting from rapid enzymatic metabolism by peptidases including angiotensin-converting enzyme (ACE) and dipeptidyl peptidase 3 (DPP 3). We report the facile assembly of three novel Ang-(1-7) analogues by solid-phase peptide synthesis which incorporates the cyclic non-natural δ-amino acid ACCA. The analogues containing the ACCA substitution at the site of ACE cleavage exhibit complete resistance to human ACE, while substitution at the DDP 3 cleavage site provided stability against DPP 3 hydrolysis. Furthermore, the analogues retain the anti-proliferative properties of Ang-(1-7) against the 4T1 and HT-1080 cancer cell lines. These results suggest that ACCA-substituted Ang-(1-7) analogues which show resistance against proteolytic degradation by peptidases known to hydrolyze the native heptapeptide may be novel therapeutics in the treatment of cancer. [Mh] Termos MeSH primário: Substituição de Aminoácidos Angiotensina I Dipeptidil Peptidases e Tripeptidil Peptidases/química Fragmentos de Peptídeos Peptidil Dipeptidase A/química Proteólise [Mh] Termos MeSH secundário: Angiotensina I/síntese química Angiotensina I/química Seres Humanos Fragmentos de Peptídeos/síntese química Fragmentos de Peptídeos/química Estabilidade Proteica [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL [Nm] Nome de substância: 0 (Peptide Fragments); 9041-90-1 (Angiotensin I); EC 3.4.14.- (Dipeptidyl-Peptidases and Tripeptidyl-Peptidases); EC 3.4.14.4 (DPP3 protein, human); EC 3.4.15.1 (Peptidyl-Dipeptidase A); IJ3FUK8MOF (angiotensin I (1-7)) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180305 [Lr] Data última revisão: 180305 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170727 [St] Status: MEDLINE [do] DOI: 10.1007/s00726-017-2471-9

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[PMID]: 29377907 [Au] Autor: Pezeshgi Modarres H; Mofrad MR; Sanati-Nezhad A [Ad] Endereço: BioMEMS and Bioinspired Microfluidic Laboratory, Department of Mechanical and Manufacturing Engineering, University of Calgary, Calgary, Alberta, Canada. [Ti] Título: ProtDataTherm: A database for thermostability analysis and engineering of proteins. [So] Source: PLoS One;13(1):e0191222, 2018. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Protein thermostability engineering is a powerful tool to improve resistance of proteins against high temperatures and thereafter broaden their applications. For efficient protein thermostability engineering, different thermostability-classified data sources including sequences and 3D structures are needed for different protein families. However, no data source is available providing such data easily. It is the first release of ProtDataTherm database for analysis and engineering of protein thermostability which contains more than 14 million protein sequences categorized based on their thermal stability and protein family. This database contains data needed for better understanding protein thermostability and stability engineering. Providing categorized protein sequences and structures as psychrophilic, mesophilic and thermophilic makes this database useful for the development of new tools in protein stability prediction. This database is available at http://profiles.bs.ipm.ir/softwares/protdatatherm. As a proof of concept, the thermostability that improves mutations were suggested for one sample protein belonging to one of protein families with more than 20 mesophilic and thermophilic sequences and with known experimentally measured ΔT of mutations available within ProTherm database. [Mh] Termos MeSH primário: Bases de Dados de Proteínas Engenharia de Proteínas Estabilidade Proteica [Mh] Termos MeSH secundário: Algoritmos Sequência de Aminoácidos Proteínas de Bactérias/química Proteínas de Bactérias/genética Temperatura Alta Modelos Moleculares Mutação Termodinâmica [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Bacterial Proteins) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180130 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0191222

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[PMID]: 29372732 [Au] Autor: Xu L; Bhattacharya S; Thompson D [Ad] Endereço: Department of Physics, Bernal Institute, University of Limerick, V94 T9PX, Ireland. Damien.thompson@ul.ie. [Ti] Título: The fold preference and thermodynamic stability of α-synuclein fibrils is encoded in the non-amyloid-ß component region. [So] Source: Phys Chem Chem Phys;20(6):4502-4512, 2018 Feb 07. [Is] ISSN: 1463-9084 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The heterogeneity of the synucleinopathies, neurological disorders that include Parkinson's disease (PD), indicates that toxicity, seeding/cross-seeding ability, and propagation of α-synuclein (αS) assemblies depend on their distinct structural characteristics or "strain". To examine the molecular signature that encodes the aggregation seed, conformational preference, and thermodynamic stability of full-length αS fibrils, we performed molecular dynamics simulations on two non-amyloid-ß component (NAC) fibril structures, containing residues 61-95 of two distinct αS fibrils. We identified several discrete hot spots in the recognized hydrophobic core of NAC (residues 68-82) that could initiate the early assembly of αS. We show that NAC fibrils inherit the preferred fold of their parent αS fibril, but could switch conformational preference in two fibril mutants K80Q and E83Q under different solution conditions. Similar to αS fibrils, NAC fibrils are also sensitive to temperature and salt concentration. The favorable solvation free energy of NAC fibrils at low temperature (280 K) suggests a propensity for cold-denaturation. Our results indicate that the strain-dependent synucleinopathies may be partially imprinted in the fold-dependent thermodynamic properties of NAC fibrils, providing structural insights into the emerging development of anti-PD treatments that target the NAC region of αS. [Mh] Termos MeSH primário: Simulação de Dinâmica Molecular alfa-Sinucleína/química [Mh] Termos MeSH secundário: Sequência de Aminoácidos Amiloide/química Seres Humanos Mutagênese Sítio-Dirigida Doença de Parkinson/metabolismo Doença de Parkinson/patologia Estabilidade Proteica Estrutura Secundária de Proteína Termodinâmica alfa-Sinucleína/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amyloid); 0 (alpha-Synuclein) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180127 [St] Status: MEDLINE [do] DOI: 10.1039/c7cp08321a

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[PMID]: 29336449 [Au] Autor: Yue Z; Shen J [Ad] Endereço: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201-1075, USA. jana.shen@rx.umaryland.edu. [Ti] Título: pH-Dependent cooperativity and existence of a dry molten globule in the folding of a miniprotein BBL. [So] Source: Phys Chem Chem Phys;20(5):3523-3530, 2018 Jan 31. [Is] ISSN: 1463-9084 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Solution pH plays an important role in protein dynamics, stability, and folding; however, detailed mechanisms remain poorly understood. Here we use continuous constant pH molecular dynamics in explicit solvent with pH replica exchange to describe the pH profile of the folding cooperativity of a miniprotein BBL, which has drawn intense debate in the past. Our data reconciled the two opposing hypotheses (downhill vs. two-state) and uncovered a sparsely populated unfolding intermediate. As pH is lowered from 7 to 5, the folding barrier vanishes. As pH continues to decrease, the unfolding barrier lowers and denaturation is triggered by the protonation of Asp162, consistent with experimental evidence. Interestingly, unfolding proceeded via an intermediate, with intact secondary structure and a compact, unlocked hydrophobic core shielded from solvent, lending support to the recent hypothesis of a universal dry molten globule in protein folding. Our work demonstrates that constant pH molecular dynamics is a unique tool for testing this and other hypotheses to advance the knowledge in protein dynamics, stability, and folding. [Mh] Termos MeSH primário: Proteínas/química [Mh] Termos MeSH secundário: Concentração de Íons de Hidrogênio Ressonância Magnética Nuclear Biomolecular Desnaturação Proteica Dobramento de Proteína Estabilidade Proteica Proteínas/metabolismo Termodinâmica [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Proteins) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180117 [St] Status: MEDLINE [do] DOI: 10.1039/c7cp08296g

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