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1.
Cell Syst ; 12(8): 780-794.e7, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34139154

RESUMO

COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease.


Assuntos
Biomarcadores/análise , COVID-19/patologia , Progressão da Doença , Proteoma/fisiologia , Fatores Etários , Contagem de Células Sanguíneas , Gasometria , Ativação Enzimática , Humanos , Inflamação/patologia , Aprendizado de Máquina , Prognóstico , Proteômica , SARS-CoV-2/imunologia
2.
J Phys Chem B ; 123(50): 10594-10604, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31702165

RESUMO

The water-soluble chlorophyll-binding protein (WSCP) is assumed to be not a part of the photosynthetic process. Applying molecular dynamics (MD) simulations, we aimed to obtain insight into the exceptional stability of WSCP. We analyzed dynamical features such as the hydrogen bond network, flexibility, and force distributions. The WSCP structure contains two cysteines at the interfaces of every protein chain, which are in close contact with the cysteines of the other dimer. We tested if a connection of these cysteines between different protein chains influences the dynamical behavior to investigate any influences on the thermal stability. We find that the hydrogen bond network is very stable regardless of the presence or absence of the hypothetical disulfide bridges and/or the chlorophyll units. Furthermore, it is found that the phytyl chains of the chlorophyll units are extremely flexible, much more than what is seen in crystal structures. Nonetheless, they seem to protect a photochemically active site of the chlorophylls over the complete simulation time. Finally, we also find that a cavity in the chlorophyll-surrounding sheath exists, which may allow access for individual small molecules to the core of WSCP.


Assuntos
Proteínas de Ligação à Clorofila/química , Proteínas de Ligação à Clorofila/metabolismo , Simulação de Dinâmica Molecular , Água/química , Ligação de Hidrogênio , Conformação Proteica , Estabilidade Proteica , Solubilidade
3.
J Chem Inf Model ; 59(1): 294-308, 2019 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-30457855

RESUMO

Cyclization and selected backbone N-methylations are found to be often necessary but not sufficient conditions for peptidic drugs to have a good bioavailability. Thus, the design of cyclic peptides with good passive membrane permeability and good solubility remains a challenge. The backbone scaffold of a recently published series of cyclic decapeptides with six selected backbone N-methylations was designed to favor the adoption of a closed conformation with ß-turns and four transannular hydrogen bonds. Although this conformation was indeed adopted by the peptides as determined by NMR measurements, substantial differences in the membrane permeability were observed. In this work, we aim to rationalize the impact of discrete side chain modifications on membrane permeability for six of these cyclic decapeptides. The thermodynamic and kinetic properties were investigated using molecular dynamics simulations and Markov state modeling in water and chloroform. The study highlights the influence that side-chain modifications can have on the backbone conformation. Peptides with a d-proline in the ß-turns were more likely to adopt, even in water, the closed conformation with transannular hydrogen bonds, which facilitates transition through the membrane. The population of the closed conformation in water was found to correlate positively with PAMPA log Pe.


Assuntos
Permeabilidade da Membrana Celular , Simulação de Dinâmica Molecular , Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismo , Ligação de Hidrogênio , Conformação Proteica , Solubilidade
4.
Inorg Chem ; 57(9): 5004-5012, 2018 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-29683319

RESUMO

Many drugs that are applied in anticancer therapy such as the anthracycline doxorubicin contain DNA-intercalating 9,10-anthraquinone (AQ) moieties. When Cu(II) cyclen complexes were functionalized with up to three (2-anthraquinonyl)methyl substituents, they efficiently inhibited DNA and RNA synthesis resulting in high cytotoxicity (selective for cancer cells) accompanied by DNA condensation/aggregation phenomena. Molecular modeling suggests an unusual bisintercalation mode with only one base pair between the two AQ moieties and the metal complex as a linker. A regioisomer, in which the AQ moieties point in directions unfavorable for such an interaction, had a much weaker biological activity. The ligands alone and corresponding Zn(II) complexes (used as redox inert control compounds) also exhibited lower activity.


Assuntos
Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cobre/química , Replicação do DNA/efeitos dos fármacos , DNA/biossíntese , RNA/biossíntese , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Cristalografia por Raios X , DNA/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Plasmídeos , RNA/química , Relação Estrutura-Atividade
5.
Chem Sci ; 8(5): 3471-3478, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28507719

RESUMO

The broad substrate tolerance of tubulin tyrosine ligase is the basic rationale behind its wide applicability for chemoenzymatic protein functionalization. In this context, we report that the wild-type enzyme enables ligation of various unnatural amino acids that are substantially bigger than and structurally unrelated to the natural substrate, tyrosine, without the need for extensive protein engineering. This unusual substrate flexibility is due to the fact that the enzyme's catalytic pocket forms an extended cavity during ligation, as confirmed by docking experiments and all-atom molecular dynamics simulations. This feature enabled one-step C-terminal biotinylation and fluorescent coumarin labeling of various functional proteins as demonstrated with ubiquitin, an antigen binding nanobody, and the apoptosis marker Annexin V. Its broad substrate tolerance establishes tubulin tyrosine ligase as a powerful tool for in vitro enzyme-mediated protein modification with single functional amino acids in a specific structural context.

7.
J Chem Phys ; 145(16): 164104, 2016 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-27802637

RESUMO

The core-set approach is a discretization method for Markov state models of complex molecular dynamics. Core sets are disjoint metastable regions in the conformational space, which need to be known prior to the construction of the core-set model. We propose to use density-based cluster algorithms to identify the cores. We compare three different density-based cluster algorithms: the CNN, the DBSCAN, and the Jarvis-Patrick algorithm. While the core-set models based on the CNN and DBSCAN clustering are well-converged, constructing core-set models based on the Jarvis-Patrick clustering cannot be recommended. In a well-converged core-set model, the number of core sets is up to an order of magnitude smaller than the number of states in a conventional Markov state model with comparable approximation error. Moreover, using the density-based clustering one can extend the core-set method to systems which are not strongly metastable. This is important for the practical application of the core-set method because most biologically interesting systems are only marginally metastable. The key point is to perform a hierarchical density-based clustering while monitoring the structure of the metric matrix which appears in the core-set method. We test this approach on a molecular-dynamics simulation of a highly flexible 14-residue peptide. The resulting core-set models have a high spatial resolution and can distinguish between conformationally similar yet chemically different structures, such as register-shifted hairpin structures.

8.
Proc Natl Acad Sci U S A ; 113(31): E4446-54, 2016 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-27418603

RESUMO

Although the sequence of primes is very well distributed in the reduced residue classes [Formula: see text], the distribution of pairs of consecutive primes among the permissible ϕ(q)(2) pairs of reduced residue classes [Formula: see text] is surprisingly erratic. This paper proposes a conjectural explanation for this phenomenon, based on the Hardy-Littlewood conjectures. The conjectures are then compared with numerical data, and the observed fit is very good.

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