pH Induced Switch in the Conformational Ensemble of an Intrinsically Disordered Protein Prothymosin-αand Its Implications to Amyloid Fibril Formation

Abstract

AbstractAggregation of intrinsically disordered proteins (IDPs) is the cause of various neu-rodegenerative diseases. Changes in solution pH can trigger IDP aggregation due to a shift in the IDP monomer population with a high aggregation propensity. Al-though there is experimental evidence that acidic pH promotes the compaction of IDP monomers, which subsequently leads to aggregation, the general mechanism is not clear. Using the IDP prothymosin-α(proTα), which is involved in multiple essential functions as a model system, we studied the pH effect on the conformational ensemble of proTαand probed its role in aggregation using a coarse-grained IDP model and molecular dynamics simulations. We show that compaction in the proTαdimension at low pH is due to the protein’s collapse in the intermediate region (E41 - D80) rich in glutamic acid residues. Further, theβ-sheet content increases in this region upon pH change from neutral to acidic. We hypothesized that the conformations with highβ-sheet content could act as aggregation-prone (N∗) states and nucleate the aggregation process. We validated our hypothesis by performing dimer simulations starting fromN∗and non-N∗states. We show that simulations initiated usingN∗states as initial conformations form dimers within 1.5μs, whereas the non-N∗states do not form dimers within this timescale. This study contributes to understanding the general principles of pH-induced IDP aggregation. The main result upon pH change from neutral to acidic, the intermediate region of proTαis responsible for aggregation due to an increase in itsβ-sheet forming propensity and forms the fibril core can be verified by experiments.Graphical TOC Entry