Transition in the Conformational Ensemble of Intrinsically Disordered Proteins: Implications for Phase Separation and Aggregation

Abstract

Intrinsically disordered proteins (IDPs) are enriched with charged and polar residues and lack a unique three-dimensional structure. Due to the high fraction of charged residues, IDPs are disordered and dynamic, transitioning between different conformations resulting in a heterogeneous conformational ensemble. Despite their dynamic nature, IDPs are involved in multiple cellular functions such as cell signaling, signal transduction, chromatin remodeling, etc. Further, the aberrant behavior of IDPs is associated with various neurodegenerative diseases and cancer through liquid-liquid phase separation (LLPS) and aggregation. The malfunction of IDPs is generally due to the subtle shift in the population of the conformations in the heterogeneous ensemble, which is dictated by intrinsic factors such as chain length, amino acid composition, sequence, net charge, mutations, etc. In addition, external parameters such as temperature, pH, salts, cosolvents, and ions also modulate the IDP ensemble. Interestingly, multichain properties of the IDPs, such as phase separation/aggregation propensity, are also encoded within their single-chain properties. These interesting IDP properties make it essential to understand how various factors influence the IDP conformational ensemble.

In this thesis, using computations and IDP coarse-grained models suitable to probe the relevant length and time scales, I studied the effects of internal (chain length, composition, and sequence) and external (salts, pH, cosolvents, ions) factors on the properties of dilute IDP solutions and predicted their implications on IDPs' LLPS/aggregation propensity.