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Disordered proteins play essential roles in myriad cellular processes, yet their structural characterization remains a major challenge due to their dynamic and heterogeneous nature. We here present a community-driven initiative to address…

We outline recent developments in artificial intelligence (AI) and machine learning (ML) techniques for integrative structural biology of intrinsically disordered proteins (IDP) ensembles. IDPs challenge the traditional protein…

Biomolecules · Quantitative Biology 2020-12-03 Arvind Ramanathan , Heng Ma , Akash Parvatikar , Chakra S. Chennubhotla

Intrinsically disordered proteins (IDPs) constitute a broad set of proteins with few uniting and many diverging properties. IDPs-and intrinsically disordered regions (IDRs) interspersed between folded domains-are generally characterized as…

Biomolecules · Quantitative Biology 2021-06-03 Kresten Lindorff-Larsen , Birthe B. Kragelund

In 1999 Wright and Dyson highlighted the fact that large sections of the proteome of all organisms are comprised of protein sequences that lack globular folded structures under physiological conditions. Since then the biophysics community…

Biological Physics · Physics 2024-09-05 Zi Hao Liu , Maria Tsanai , Oufan Zhang , Julie Forman-Kay , Teresa Head-Gordon

A protein's function depends critically on its conformational ensemble, a collection of energy weighted structures whose balance depends on temperature and environment. Though recent deep learning (DL) methods have substantially advanced…

Biomolecules · Quantitative Biology 2026-01-09 Myeongsang Lee , Lauren L. Porter

Accurate protein structural ensembles can be determined with metainference, a Bayesian inference method that integrates experimental information with prior knowledge of the system and deals with all sources of uncertainty and errors as well…

Quantitative Methods · Quantitative Biology 2019-01-24 Thomas Löhr , Carlo Camilloni , Massimiliano Bonomi , Michele Vendruscolo

All-atom molecular dynamics (MD) computer simulations are a valuable tool for characterizing the conformational ensembles of intrinsically disordered proteins (IDPs). IDP conformational ensembles are highly heterogeneous and contain…

Chemical Physics · Physics 2025-05-06 Jaya Krishna Koneru , Korey M. Reid , Paul Robustelli

The paradigm that the primary amino acid sequence prescribes structure and thus function has for a long time been central to the understanding of protein science. Though the theory is supported by the behaviour of most structured proteins,…

Biological Physics · Physics 2022-12-19 Rickie Xian , Sarah Rauscher

Protein design has the potential to revolutionize biotechnology and medicine. While most efforts have focused on proteins with well-defined structures, increased recognition of the functional significance of intrinsically disordered…

Biomolecules · Quantitative Biology 2025-09-17 Giulio Tesei , Francesco Pesce , Kresten Lindorff-Larsen

Intrinsically disordered proteins (IDPs) do not possess well-defined three-dimensional structures in solution under physiological conditions. We develop all-atom, united-atom, and coarse-grained Langevin dynamics simulations for the IDP…

Intrinsically disordered proteins and regions are increasingly appreciated for their abundance in the proteome and the many functional roles they play in the cell. In this short review, we describe a variety of approaches used to obtain…

Biological Physics · Physics 2024-12-31 Zi Hao Liu , Maria Tsanai , Oufan Zhang , Teresa Head-Gordon , Julie Forman-Kay

Intrinsically Disordered Proteins (IDPs) constitute a large and structure-less class of proteins with significant functions. The existence of IDPs challenges the conventional notion that the biological functions of proteins rely on their…

Biomolecules · Quantitative Biology 2024-11-26 Parisa Mollaei , Danush Sadasivam , Chakradhar Guntuboina , Amir Barati Farimani

Intrinsically disordered proteins (IDPs) are important for biological functions. In contrast to folded proteins, molecular recognition among certain IDPs is "fuzzy" in that their binding and/or phase separation are stochastically governed…

Biomolecules · Quantitative Biology 2020-08-10 Alan N. Amin , Yi-Hsuan Lin , Suman Das , Hue Sun Chan

Many pairwise additive force fields are in active use for intrinsically disordered proteins (IDPs) and regions (IDRs), some of which modify energetic terms to improve description of IDPs/IDRs, but are largely in disagreement with solution…

It is becoming clear that traditional, single-structure models of proteins are insufficient for understanding their biological function. Here, we outline one method for inferring, from experiments, not only the most common structure a…

Biological Physics · Physics 2014-08-04 Thomas J. Lane , Christian R. Schwantes , Kyle A. Beauchamp , Vijay S. Pande

Synthetic copolymers and biopolymers, such as polypeptides and double-stranded DNA, often exhibit strong variations in bending stiffness along their contour, which can significantly impact conformational behavior at larger scales. To…

Soft Condensed Matter · Physics 2025-11-04 Yannick Witzky , Friederike Schmid , Arash Nikoubashman

Proteins exist as a dynamic ensemble of multiple conformations, and these motions are often crucial for their functions. However, current structure prediction methods predominantly yield a single conformation, overlooking the conformational…

Biomolecules · Quantitative Biology 2025-06-18 Advaith Maddipatla , Nadav Bojan Sellam , Meital Bojan , Sanketh Vedula , Paul Schanda , Ailie Marx , Alex M. Bronstein

Proteins are dynamic, adopting ensembles of conformations. The nature of this conformational heterogenity is imprinted in the raw electron density measurements obtained from X-ray crystallography experiments. Fitting an ensemble of protein…

Quantitative Methods · Quantitative Biology 2024-12-19 Sai Advaith Maddipatla , Nadav Bojan Sellam , Sanketh Vedula , Ailie Marx , Alex Bronstein

Achieving a comprehensive understanding of the behaviour of proteins is greatly facilitated by the knowledge of their structures, thermodynamics and dynamics. All this information can be provided in an effective manner in terms of…

Quantitative Methods · Quantitative Biology 2019-03-27 Massimiliano Bonomi , Michele Vendruscolo

The human proteome is enriched in proteins that do not fold into a stable 3D structure. These intrinsically disordered proteins (IDPs) spontaneously fluctuate between a large number of configurations in their native form. Remarkably, the…

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