Full structural ensembles of intrinsically disordered proteins from unbiased molecular dynamics simulations

Shrestha, Utsab R.; Smith, Jeremy C.; Petridis, Loukas

doi:10.1038/s42003-021-01759-1

Cited by 74 publications

(60 citation statements)

References 101 publications

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“…4B and S11). The lower Pearson’s correlation coefficients observed for ν , compared to the corresponding R g data, may originate from the different forward models used to infer ν from SAXS experiments and simulation data, i.e., respectively, the molecular form factor method (16, 48) and least-squares fit to long intramolecular pairwise distances, R ij , vs | i − j | > 10 (56) (Fig. S12).…”

Section: Resultsmentioning

confidence: 99%

Accurate model of liquid-liquid phase behaviour of intrinsically-disordered proteins from optimization of single-chain properties

Tesei¹,

Schulze²,

Crehuet

et al. 2021

Preprint

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Many intrinsically disordered proteins (IDPs) may undergo liquid-liquid phase separation (LLPS) and participate in the formation of membraneless organelles in the cell, thereby contributing to the regulation and compartmentalisation of intracellular biochemical reactions. The phase behaviour of IDPs is sequence-dependent, and its investigation through molecular simulations requires protein models that combine computational efficiency with an accurate description of intra- and intermolecular interactions. We developed a general coarse-grained model of IDPs, with residue-level detail, based on an extensive set of experimental data on single-chain properties. Ensemble-averaged experimental observables are predicted from molecular simulations, and a data-driven parameter-learning procedure is used to identify the residue-specific model parameters that minimize the discrepancy between predictions and experiments. The model accurately reproduces the experimentally observed conformational propensities of a set of IDPs. Through two-body as well as large-scale molecular simulations, we show that the optimization of the intramolecular interactions results in improved predictions of protein self-association and LLPS.

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Section: Resultsmentioning

confidence: 99%

Accurate model of liquid-liquid phase behaviour of intrinsically-disordered proteins from optimization of single-chain properties

Tesei¹,

Schulze²,

Crehuet

et al. 2021

Preprint

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show abstract

“…REST has proven to be one of the most reliable choices for enhanced sampling of protein folding and particularly disordered conformational ensembles [113,114]. Sugita and co-workers leveraged gREST to target the dihedral-angle energy term and successfully sampled folding transitions of beta-hairpins and Trp-cage in explicit water, using fewer replicas but covering wider conformational space compared to REST2 [84].…”

Section: Collective Variables-free Sampling Methods and Optimizationmentioning

confidence: 99%

Advanced Sampling Methods for Multiscale Simulation of Disordered Proteins and Dynamic Interactions

Gong

Chen

2021

Biomolecules

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Intrinsically disordered proteins (IDPs) are highly prevalent and play important roles in biology and human diseases. It is now also recognized that many IDPs remain dynamic even in specific complexes and functional assemblies. Computer simulations are essential for deriving a molecular description of the disordered protein ensembles and dynamic interactions for a mechanistic understanding of IDPs in biology, diseases, and therapeutics. Here, we provide an in-depth review of recent advances in the multi-scale simulation of disordered protein states, with a particular emphasis on the development and application of advanced sampling techniques for studying IDPs. These techniques are critical for adequate sampling of the manifold functionally relevant conformational spaces of IDPs. Together with dramatically improved protein force fields, these advanced simulation approaches have achieved substantial success and demonstrated significant promise towards the quantitative and predictive modeling of IDPs and their dynamic interactions. We will also discuss important challenges remaining in the atomistic simulation of larger systems and how various coarse-grained approaches may help to bridge the remaining gaps in the accessible time- and length-scales of IDP simulations.

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“…Whereas molecular dynamics (MD) simulations using all-atom physics-based force field models are widely used for the investigation of interactions involving globular proteins, the applicability of “standard” MD approaches to IDPs/IDRs is relatively limited [37] , [48] . A first limitation comes from the fact that force fields, such as Amber and CHARMM, were mostly developed having globular proteins as targets.…”

Section: An Overview Of Computational Approachesmentioning

confidence: 99%

The diversity of molecular interactions involving intrinsically disordered proteins: A molecular modeling perspective

Clerc

Sagar

Barducci

et al. 2021

Computational and Structural Biotechnology Journal

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Intrinsically Disordered Proteins and Regions (IDPs/IDRs) are key components of a multitude of biological processes. Conformational malleability enables IDPs/IDRs to perform very specialized functions that cannot be accomplished by globular proteins. The functional role for most of these proteins is related to the recognition of other biomolecules to regulate biological processes or as a part of signaling pathways. Depending on the extent of disorder, the number of interacting sites and the type of partner, very different architectures for the resulting assemblies are possible. More recently, molecular condensates with liquid-like properties composed of multiple copies of IDPs and nucleic acids have been proven to regulate key processes in eukaryotic cells. The structural and kinetic details of disordered biomolecular complexes are difficult to unveil experimentally due to their inherent conformational heterogeneity. Computational approaches, alone or in combination with experimental data, have emerged as unavoidable tools to understand the functional mechanisms of this elusive type of assemblies. The level of description used, all-atom or coarse-grained, strongly depends on the size of the molecular systems and on the timescale of the investigated mechanism. In this mini-review, we describe the most relevant architectures found for molecular interactions involving IDPs/IDRs and the computational strategies applied for their investigation.

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Full structural ensembles of intrinsically disordered proteins from unbiased molecular dynamics simulations

Cited by 74 publications

References 101 publications

Accurate model of liquid-liquid phase behaviour of intrinsically-disordered proteins from optimization of single-chain properties

Accurate model of liquid-liquid phase behaviour of intrinsically-disordered proteins from optimization of single-chain properties

Advanced Sampling Methods for Multiscale Simulation of Disordered Proteins and Dynamic Interactions

The diversity of molecular interactions involving intrinsically disordered proteins: A molecular modeling perspective

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