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Abstract Intrinsically disordered regions (IDRs) are ubiquitous across all domains of life and play a range of functional roles. While folded domains are generally well described by a stable three-dimensional structure, IDRs exist in a collection of interconverting states known as an ensemble. This structural heterogeneity means that IDRs are largely absent from the Protein Data Bank, contributing to a lack of computational approaches to predict ensemble conformational properties from sequence. Here we combine rational sequence design, large-scale molecular simulations and deep learning to develop ALBATROSS, a deep-learning model for predicting ensemble dimensions of IDRs, including the radius of gyration, end-to-end distance, polymer-scaling exponent and ensemble asphericity, directly from sequences at a proteome-wide scale. ALBATROSS is lightweight, easy to use and accessible as both a locally installable software package and a point-and-click-style interface via Google Colab notebooks. We first demonstrate the applicability of our predictors by examining the generalizability of sequence–ensemble relationships in IDRs. Then, we leverage the high-throughput nature of ALBATROSS to characterize the sequence-specific biophysical behavior of IDRs within and between proteomes.
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Sequence-ensemble-function relationships for disordered proteins in live cells
ABSTRACT Intrinsically disordered protein regions (IDRs) are ubiquitous across all kingdoms of life and play a variety of essential cellular roles. IDRs exist in a collection of structurally distinct conformers known as an ensemble. An IDR’s amino acid sequence determines its ensemble, which in turn can play an important role in dictating molecular function. Yet a clear link connecting IDR sequence, its ensemble properties, and its molecular function in living cells has not been directly established. Here, we set out to test this sequence-ensemble-function paradigm using a novel computational method (GOOSE) that enables the rational design of libraries of IDRs by systematically varying specific sequence properties. Using ensemble FRET, we measured the ensemble dimensions of a library of rationally designed IDRs in human-derived cell lines, revealing how IDR sequence influences ensemble dimensionsin situ.Furthermore, we show that the interplay between sequence and ensemble can tune an IDR’s ability to sense changes in cell volume - ade novomolecular function for these synthetic sequences. Our results establish biophysical rules for intracellular sequence-ensemble relationships, enable a new route for understanding how IDR sequences map to function in live cells, and set the ground for the design of synthetic IDRs withde novofunction.
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- PAR ID:
- 10528469
- Publisher / Repository:
- bioRxiv
- Date Published:
- Format(s):
- Medium: X
- Institution:
- bioRxiv
- Sponsoring Org:
- National Science Foundation
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Accepted Manuscript1.0
- Posted Content:
- https://doi.org/10.1101/2023.10.29.564547
