Conformational ensembles of intrinsically disordered proteins and flexible multidomain proteins

TL;DR

This review discusses current methods for determining conformational ensembles of intrinsically disordered and multidomain proteins, integrating experimental data and computational models to understand their structural heterogeneity.

Contribution

It provides a comprehensive overview of approaches, models, and recent applications for ensemble determination of flexible proteins, highlighting future research directions.

Findings

Various biophysical experiments inform ensemble determination.

Computational models sample diverse conformations.

Integrative methods improve understanding of protein flexibility.

Abstract

Intrinsically disordered proteins (IDPs) and multidomain proteins with flexible linkers show a high level of structural heterogeneity and are best described by ensembles consisting of multiple conformations with associated thermodynamic weights. Determining conformational ensembles usually involves integration of biophysical experiments and computational models. In this review, we discuss current approaches to determining conformational ensembles of IDPs and multidomain proteins, including the choice of biophysical experiments, computational models used to sample protein conformations, models to calculate experimental observables from protein structure, and methods to refine ensembles against experimental data. We also provide examples of recent applications of integrative conformational ensemble determination to study IDPs and multidomain proteins and suggest future directions for research in the field.