Structural biases in disordered proteins are prevalent in the cell

Moses, David; Guadalupe, Karina; Yu, Feng; Flores, Eduardo; Perez, Anthony; McAnelly, Ralph; Shamoon, Nora M.; Cuevas-Zepeda, Estefania; Merg, Andrea D.; Martin, Erik W.; Holehouse, Alex S.; Sukenik, Shahar

doi:10.1101/2021.11.24.469609

Cited by 24 publications

(36 citation statements)

References 107 publications

(242 reference statements)

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“…SOURSOP contains a range of additional routines not explored in this work but have been applied to various systems under a range of contexts, including local residual structure, intra-residue contacts, and the interaction between folded and disordered regions (Fig. S1) 57,58,[85][86][87] .…”

Section: Discussionmentioning

confidence: 99%

“…Under this model, each residue is equivalently solvent-accessible, and IDRs can be thought of as flexible scaffolds where the relative position along the chain has no real impact on molecular accessibility. While this is an appealingly simple model, given the complex conformational behavior observed in our analyses here and elsewhere, it may not be a given that every residue is equally accessible 58,70,[79][80][81][82] . To examine this idea further, we computed local accessibility across eight-residue windows for each IDR using a 10 Å spherical probe (Fig.…”

Section: Molecular Accessibility Is Context Dependent In Idrsmentioning

confidence: 91%

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SOURSOP: A Python package for the analysis of simulations of intrinsically disordered proteins

Lalmansingh

Keeley

Ruff

et al. 2023

Preprint

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Conformational heterogeneity is a defining hallmark of intrinsically disordered proteins and protein regions (IDRs). The functions of IDRs and the emergent cellular phenotypes they control are associated with sequence-specific conformational ensembles. Simulations of conformational ensembles that are based on atomistic and coarse-grained models are routinely used to uncover the sequence-specific interactions that may contribute to IDR functions. These simulations are performed either independently or in conjunction with data from experiments. Functionally relevant features of IDRs can span a range of length scales. Extracting these features requires analysis routines that quantify a range of properties. Here, we describe a new analysis suite SOURSOP, an object-oriented and open-source toolkit designed for the analysis of simulated conformational ensembles of IDRs. SOURSOP implements several analysis routines motivated by principles in polymer physics, offering a unique collection of simple-to-use functions to characterize IDR ensembles. As an extendable framework, SOURSOP supports the development and implementation of new analysis routines that can be easily packaged and shared.

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Section: Discussionmentioning

confidence: 99%

Section: Molecular Accessibility Is Context Dependent In Idrsmentioning

confidence: 91%

SOURSOP: A Python package for the analysis of simulations of intrinsically disordered proteins

Lalmansingh

Keeley

Ruff

et al. 2023

Preprint

Self Cite

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“…What are properties that separate the optimal matrices from generic ones? Answering this question is directly relevant to biomolecular condensates, where hidden structures in intrinsically disordered regions might strongly affect the phase behavior of proteins ( 49 ). Another question concerns the composition of phases resulting from optimal interactions.…”

Section: Discussionmentioning

confidence: 99%

Evolved interactions stabilize many coexisting phases in multicomponent liquids

Zwicker

Laan

2022

Proc. Natl. Acad. Sci. U.S.A.

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Phase separation has emerged as an essential concept for the spatial organization inside biological cells. However, despite the clear relevance to virtually all physiological functions, we understand surprisingly little about what phases form in a system of many interacting components, like in cells. Here we introduce a numerical method based on physical relaxation dynamics to study the coexisting phases in such systems. We use our approach to optimize interactions between components, similar to how evolution might have optimized the interactions of proteins. These evolved interactions robustly lead to a defined number of phases, despite substantial uncertainties in the initial composition, while random or designed interactions perform much worse. Moreover, the optimized interactions are robust to perturbations, and they allow fast adaption to new target phase counts. We thus show that genetically encoded interactions of proteins provide versatile control of phase behavior. The phases forming in our system are also a concrete example of a robust emergent property that does not rely on fine-tuning the parameters of individual constituents.

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“…Similarly, in alpha-synuclein (Asyn), the corresponding ratios were 0.7 and 0.9, again reporting a smaller end-to-end distance than radius of gyration. As suggested previously, discrepancies in end-to-end distance vs. radius of gyration vs. expectations from homopolymer models are diagnostic of sequence-encoded conformational biases 18,35,36,79 . report the average distance between each pair of residues (i,j) divided by the distance expected for an AFRC-derived distance map, providing a unitless parameter that varies between 0.7 and 1.3 in these simulations.…”

Section: Comparison With All-atom Simulationsmentioning

confidence: 53%

The analytical Flory random coil is a simple-to-use reference model for unfolded and disordered proteins

Alston

Ginell

Soranno

et al. 2023

Preprint

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Denatured, unfolded, and intrinsically disordered proteins (collectively referred to here as unfolded proteins) can be described using analytical polymer models. These models capture various polymeric properties and can be fit to simulation results or experimental data. However, the model parameters commonly require users' decisions, making them useful for data interpretation but less clearly applicable as stand-alone reference models. Here we use all-atom simulations of polypeptides in conjunction with polymer scaling theory to parameterize an analytical model of unfolded polypeptides that behave as ideal chains (ν= 0.50). The model, which we call the analytical Flory Random Coil (AFRC), requires only the amino acid sequence as input and provides direct access to probability distributions of global and local conformational order parameters. The model defines a specific reference state to which experimental and computational results can be compared and normalized. As a proof-of-concept, we use the AFRC to identify sequence-specific intramolecular interactions in simulations of disordered proteins. We also use the AFRC to contextualize a curated set of 145 different radii of gyration obtained from previously published small-angle X-ray scattering experiments of disordered proteins. The AFRC is implemented as a stand-alone software package and is also available via a Google colab notebook. In summary, the AFRC provides a simple-to-use reference polymer model that can guide intuition and aid in interpreting experimental or simulation results.

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Structural biases in disordered proteins are prevalent in the cell

Cited by 24 publications

References 107 publications

SOURSOP: A Python package for the analysis of simulations of intrinsically disordered proteins

SOURSOP: A Python package for the analysis of simulations of intrinsically disordered proteins

Evolved interactions stabilize many coexisting phases in multicomponent liquids

The analytical Flory random coil is a simple-to-use reference model for unfolded and disordered proteins

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