Physicochemical Properties of Cells and Their Effects on Intrinsically Disordered Proteins (IDPs)

Theillet, François‐Xavier; Binolfi, Andrés; Frembgen-Kesner, Tamara; Hingorani, Karan S.; Sarkar, Mohona; Kyne, Ciara; Li, Conggang; Crowley, Peter B.; Gierasch, Lila M.; Pielak, Gary J.; Elcock, Adrian H.; Gershenson, Anne; Selenko, Philipp

doi:10.1021/cr400695p

Cited by 402 publications

(471 citation statements)

References 964 publications

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“…How these factors influence proteinprotein interactions and biomolecular processes such as folding, binding, and aggregation is a topic attracting increasing interest. [1][2][3][4][5] It is well established that excluded-volume interactions with crowder particles can have a significant stabilizing effect on globular proteins, as demonstrated by experiments with synthetic crowding agents such as Ficoll or dextran. 6 Today, experiments are increasingly often performed under more realistic crowding conditions, using concentrated protein solutions [7][8][9][10] or cells.…”

Section: Introductionmentioning

confidence: 99%

Equilibrium simulation of trp-cage in the presence of protein crowders

Bille

Linse

Mohanty

et al. 2015

The Journal of Chemical Physics

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Link to publication Citation for published version (APA): Bille, A., Linse, B., Mohanty, S., & Irbäck, A. (2015). Equilibrium simulation of trp-cage in the presence of protein crowders. Journal of Chemical Physics, 143(17), [175102]. DOI: 10.1063/1.4934997General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. While steric crowders tend to stabilize globular proteins, it has been found that protein crowders can have an either stabilizing or destabilizing effect, where a destabilization may arise from nonspecific attractive interactions between the test protein and the crowders. Here, we use Monte Carlo replicaexchange methods to explore the equilibrium behavior of the miniprotein trp-cage in the presence of protein crowders. Our results suggest that the surrounding crowders prevent trp-cage from adopting its global native fold, while giving rise to a stabilization of its main secondary-structure element, an α-helix. With the crowding agent used (bovine pancreatic trypsin inhibitor), the trp-cage-crowder interactions are found to be specific, involving a few key residues, most of which are prolines. The effects of these crowders are contrasted with those of hard-sphere crowders. C 2015 AIP Publishing LLC. Equilibrium simulation of trp-cage in the presence of protein crowders[http://dx

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Section: Introductionmentioning

confidence: 99%

Equilibrium simulation of trp-cage in the presence of protein crowders

Bille

Linse

Mohanty

et al. 2015

The Journal of Chemical Physics

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“…The development of models of IDPs within the cytoplasm will be highly desirable to understand how the structural heterogeneity of and interaction between cellular components influence IDP stability, aggregation propensity, and, consequently, the progression of neurological disorders and cancer (Theillet et al 2014;Terakawa et al 2014;Bai et al 2017). Such models are expected to contribute also to understanding the specific behaviors of the different NBs, provided that the necessary physicochemical details are included in their parameterization.…”

Section: Toward Realistic Molecular Simulations Of Cellular Eventsmentioning

confidence: 99%

Molecular simulations of cellular processes

Trovato

Fumagalli

2017

Biophys Rev

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It is, nowadays, possible to simulate biological processes in conditions that mimic the different cellular compartments. Several groups have performed these calculations using molecular models that vary in performance and accuracy. In many cases, the atomistic degrees of freedom have been eliminated, sacrificing both structural complexity and chemical specificity to be able to explore slow processes. In this review, we will discuss the insights gained from computer simulations on macromolecule diffusion, nuclear body formation, and processes involving the genetic material inside cell-mimicking spaces. We will also discuss the challenges to generate new models suitable for the simulations of biological processes on a cell scale and for cellcycle-long times, including non-equilibrium events such as the co-translational folding, misfolding, and aggregation of proteins. A prominent role will be played by the wise choice of the structural simplifications and, simultaneously, of a relatively complex energetic description. These challenging tasks will rely on the integration of experimental and computational methods, achieved through the application of efficient algorithms.

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“…These structured elements can exist in the free protein, emerging upon conformational transitions or the combinations of both. [18][19][20] The order-disordered transitions suffered by IDPs can be produced by several factors such as exogenous perturbations (for instance pH, [21][22][23] Tª 22,[24][25][26] or macromolecular crowding) 23,[27][28][29][30] or binding (multiple) diverse molecular entities, such as proteins 18,31,32 or small molecules. 10,[33][34][35] As they are very promiscuous molecules, IDPs can bind multiple partners.…”

Section: Intrinsically Disordered Proteinsmentioning

confidence: 99%

Intrinsically Disordered Proteins as Drug Targets

Martinez¹

2017

MOJPB

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Intrinsically disordered proteins (IDPs) are characterized by a lack of folded structure. Since their identification more than a decade ago, they were designed as potential drug targets. However, nowadays, only few therapeutic molecules have been designed against them. Due to the nature of these proteins bioinformatics methods could have a key role disentangling IDPs related issues, which is key to design new therapeutic agents against them.

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Physicochemical Properties of Cells and Their Effects on Intrinsically Disordered Proteins (IDPs)

Cited by 402 publications

References 964 publications

Equilibrium simulation of trp-cage in the presence of protein crowders

Equilibrium simulation of trp-cage in the presence of protein crowders

Molecular simulations of cellular processes

Intrinsically Disordered Proteins as Drug Targets

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