Recent Developments in Data-Assisted Modeling of Flexible Proteins

Many proteins can fold into well-defined conformations. However, intrinsically-disordered proteins (IDPs) do not possess a defined structure. Moreover, folded multi-domain proteins often digress into alternative conformations. Collectively, the conformational dynamics enables these proteins to fulfill specific functions. Thus, most experimental observables are averaged over the conformations that constitute an ensemble. In this article, we review the recent developments in the concept and methods for the determination of the dynamic structures of flexible peptides and proteins. In particular, we describe ways to extract information from nuclear magnetic resonance small-angle X-ray scattering (SAXS), and chemical cross-linking coupled with mass spectroscopy (XL-MS) measurements. All these techniques can be used to obtain ensemble-averaged restraints or to re-weight the simulated conformational ensembles.

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Improving the global dimensions of intrinsically disordered proteins in Martini 3

10.1101/2021.10.01.462803 ◽

2021 ◽

Author(s):

F. Emil Thomasen ◽

Francesco Pesce ◽

Mette Ahrensback Roesgaard ◽

Giulio Tesei ◽

Kresten Lindorff-Larsen

Keyword(s):

Molecular Dynamics ◽

Intrinsically Disordered Proteins ◽

Coarse Grained ◽

Disordered Proteins ◽

Saxs Data ◽

X Ray ◽

Conformational Ensembles ◽

Intrinsically Disordered ◽

X Ray Scattering ◽

Dynamics Simulations

AbstractCoarse-grained molecular dynamics simulations are a useful tool to determine conformational ensembles of intrinsically disordered proteins (IDPs). Here, we show that the coarse-grained force field Martini 3 underestimates the global dimensions of IDPs when compared with small angle X-ray scattering (SAXS) data. Increasing the strength of protein-water interactions favors more expanded conformations, improving agreement with SAXS data and alleviating problems with overestimated IDP-IDP interactions.

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A Unified De Novo Approach for Predicting the Structures of Ordered and Disordered Proteins

10.1101/2020.01.30.925636 ◽

2020 ◽

Cited By ~ 1

Author(s):

John J. Ferrie ◽

E. James Petersson

Keyword(s):

Intrinsically Disordered Proteins ◽

De Novo ◽

State Of The Art ◽

Md Simulations ◽

Disordered Proteins ◽

Conformational Ensembles ◽

Intrinsically Disordered ◽

Structural Ensembles ◽

Recent Developments ◽

Fold Prediction

AbstractAs recognition of the abundance and relevance of intrinsically disordered proteins (IDPs) continues to grow, demand increases for methods that can rapidly predict the conformational ensembles populated by these proteins. To date, IDP simulations have largely been dominated by molecular dynamics (MD) simulations, which require significant compute times and/or complex hardware. Recent developments in MD have afforded methods capable of simulating both ordered and disordered proteins, yet to date accurate fold prediction from sequence has been dominated by Monte-Carlo (MC) based methods such as Rosetta. To overcome the limitations of current approaches in IDP simulation using Rosetta while maintaining its utility for modeling folded domains, we developed PyRosetta-based algorithms that allow for the accurate de novo prediction of proteins across all degrees of foldedness along with structural ensembles of disordered proteins. Our simulations have an accuracy comparable to state-of-the-art MD with vastly reduced computational demands.

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Spontaneous Switching among Conformational Ensembles in Intrinsically Disordered Proteins

Biomolecules ◽

10.3390/biom9030114 ◽

2019 ◽

Vol 9 (3) ◽

pp. 114 ◽

Cited By ~ 14

Author(s):

Ucheor Choi ◽

Hugo Sanabria ◽

Tatyana Smirnova ◽

Mark Bowen ◽

Keith Weninger

Keyword(s):

Intrinsically Disordered Proteins ◽

Conformational Dynamics ◽

Thermal Fluctuations ◽

Amino Acid Sequences ◽

Conformational Space ◽

Disordered Proteins ◽

Conformational Ensembles ◽

Intrinsically Disordered ◽

Wide Range ◽

Polymer Models

The common conception of intrinsically disordered proteins (IDPs) is that they stochastically sample all possible configurations driven by thermal fluctuations. This is certainly true for many IDPs, which behave as swollen random coils that can be described using polymer models developed for homopolymers. However, the variability in interaction energy between different amino acid sequences provides the possibility that some configurations may be strongly preferred while others are forbidden. In compact globular IDPs, core hydration and packing density can vary between segments of the polypeptide chain leading to complex conformational dynamics. Here, we describe a growing number of proteins that appear intrinsically disordered by biochemical and bioinformatic characterization but switch between restricted regions of conformational space. In some cases, spontaneous switching between conformational ensembles was directly observed, but few methods can identify when an IDP is acting as a restricted chain. Such switching between disparate corners of conformational space could bias ligand binding and regulate the volume of IDPs acting as structural or entropic elements. Thus, mapping the accessible energy landscape and capturing dynamics across a wide range of timescales are essential to recognize when an IDP is acting as such a switch.

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Investigating the Conformational Ensembles of Intrinsically-Disordered Proteins with a Simple Physics-Based Model

10.1101/2020.02.11.943969 ◽

2020 ◽

Author(s):

Yani Zhao ◽

Robinson Cortes-Huerto ◽

Kurt Kremer ◽

Joseph F. Rudzinski

Keyword(s):

Intrinsically Disordered Proteins ◽

Conformational Dynamics ◽

Coarse Grained ◽

Disordered Proteins ◽

Side Chain ◽

Conformational Ensemble ◽

Single Chain ◽

Conformational Ensembles ◽

Intrinsically Disordered ◽

The Impact

Intrinsically disordered proteins (IDPs) play an important role in an array of biological processes but present a number of fundamental challenges for computational modeling. Recently, simple polymer models have re-gained popularity for interpreting the experimental characterization of IDPs. Homopolymer theory provides a strong foundation for understanding generic features of phenomena ranging from single-chain conformational dynamics to the properties of entangled polymer melts, but is difficult to extend to the copolymer context. This challenge is magnified for proteins due to the variety of competing interactions and large deviations in side-chain properties. In this work, we apply a simple physics-based coarse-grained model for describing largely disordered conformational ensembles of peptides, based on the premise that sampling sterically-forbidden conformations can compromise the faithful description of both static and dynamical properties. The Hamiltonian of the employed model can be easily adjusted to investigate the impact of distinct interactions and sequence specificity on the randomness of the resulting conformational ensemble. In particular, starting with a bead-spring-like model and then adding more detailed interactions one by one, we construct a hierarchical set of models and perform a detailed comparison of their properties. Our analysis clarifies the role of generic attractions, electrostatics and side-chain sterics, while providing a foundation for developing efficient models for IDPs that retain an accurate description of the hierarchy of conformational dynamics, which is nontrivially influenced by interactions with surrounding proteins and solvent molecules.

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Exploring Curated Conformational Ensembles of Intrinsically Disordered Proteins in the Protein Ensemble Database

Current Protocols ◽

10.1002/cpz1.192 ◽

2021 ◽

Vol 1 (7) ◽

Author(s):

Federica Quaglia ◽

Tamas Lazar ◽

András Hatos ◽

Peter Tompa ◽

Damiano Piovesan ◽

...

Keyword(s):

Intrinsically Disordered Proteins ◽

Disordered Proteins ◽

Conformational Ensembles ◽

Intrinsically Disordered

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Quantitative Determination of the Conformational Properties of Partially Folded and Intrinsically Disordered Proteins Using NMR Dipolar Couplings

Structure ◽

10.1016/j.str.2009.08.001 ◽

2009 ◽

Vol 17 (9) ◽

pp. 1169-1185 ◽

Cited By ~ 127

Author(s):

Malene Ringkjøbing Jensen ◽

Phineus R.L. Markwick ◽

Sebastian Meier ◽

Christian Griesinger ◽

Markus Zweckstetter ◽

...

Keyword(s):

Quantitative Determination ◽

Intrinsically Disordered Proteins ◽

Dipolar Couplings ◽

Disordered Proteins ◽

Intrinsically Disordered ◽

Conformational Properties

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Molecular simulations of protein disorderThis paper is one of a selection of papers published in this special issue entitled “Canadian Society of Biochemistry, Molecular & Cellular Biology 52nd Annual Meeting — Protein Folding: Principles and Diseases” and has undergone the Journal's usual peer review process.

Biochemistry and Cell Biology ◽

10.1139/o09-169 ◽

2010 ◽

Vol 88 (2) ◽

pp. 269-290 ◽

Cited By ~ 58

Author(s):

Sarah Rauscher ◽

Régis Pomès

Keyword(s):

Intrinsically Disordered Proteins ◽

Peer Review Process ◽

Structural Heterogeneity ◽

Disordered Proteins ◽

Cellular Biology ◽

Protein Disorder ◽

Conformational Ensembles ◽

Intrinsically Disordered ◽

Simulation Techniques ◽

Selection Of

Protein disorder is abundant in proteomes throughout all kingdoms of life and serves many biologically important roles. Disordered states of proteins are challenging to study experimentally due to their structural heterogeneity and tendency to aggregate. Computer simulations, which are not impeded by these properties, have recently emerged as a useful tool to characterize the conformational ensembles of intrinsically disordered proteins. In this review, we provide a survey of computational studies of protein disorder with an emphasis on the interdisciplinary nature of these studies. The application of simulation techniques to the study of disordered states is described in the context of experimental and bioinformatics approaches. Experimental data can be incorporated into simulations, and simulations can provide predictions for experiment. In this way, simulations have been integrated into the existing methodologies for the study of disordered state ensembles. We provide recent examples of simulations of disordered states from the literature and our own work. Throughout the review, we emphasize important predictions and biophysical understanding made possible through the use of simulations. This review is intended as both an overview and a guide for structural biologists and theoretical biophysicists seeking accurate, atomic-level descriptions of disordered state ensembles.

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From folding to function: complex macromolecular reactions unraveled one-by-one with optical tweezers

Essays in Biochemistry ◽

10.1042/ebc20200024 ◽

2021 ◽

Author(s):

Pétur O. Heidarsson ◽

Ciro Cecconi

Keyword(s):

Optical Tweezers ◽

Single Molecule ◽

Structural Changes ◽

Intrinsically Disordered Proteins ◽

Conformational Dynamics ◽

Disordered Proteins ◽

Kinase Activation ◽

Intrinsically Disordered ◽

Complex Protein ◽

Methodological Principles

Abstract Single-molecule manipulation with optical tweezers has uncovered macromolecular behaviour hidden to other experimental techniques. Recent instrumental improvements have made it possible to expand the range of systems accessible to optical tweezers. Beyond focusing on the folding and structural changes of isolated single molecules, optical tweezers studies have evolved into unraveling the basic principles of complex molecular processes such as co-translational folding on the ribosome, kinase activation dynamics, ligand–receptor binding, chaperone-assisted protein folding, and even dynamics of intrinsically disordered proteins (IDPs). In this mini-review, we illustrate the methodological principles of optical tweezers before highlighting recent advances in studying complex protein conformational dynamics – from protein synthesis to physiological function – as well as emerging future issues that are beginning to be addressed with novel approaches.

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