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

Aggregation 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- (proT), which is involved in multiple essential functions as a model system, we studied the pH effect on the conformational ensemble of proT and probed its role in aggregation using a coarse-grained IDP model and molecular dynamics simulations. We show that compaction in the proT dimension at low pH is due to the proteins collapse in the intermediate region (E41 - D80) rich in glutamic acid residues. Further, the {beta}-sheet content increases in this region upon pH change from neutral to acidic. We hypothesized that the conformations with high {beta}-sheet content could act as aggregation-prone (N*) states and nucleate the aggregation process. We validated our hypothesis by performing dimer simulations starting from N* and non-N* states. We show that simulations initiated using N* states as initial conformations form dimers within 1.5 s, 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 proT is responsible for aggregation due to an increase in its {beta}-sheet forming propensity and forms the fibril core can be verified by experiments. Graphical TOC Entry O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/497626v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@19971beorg.highwire.dtl.DTLVardef@fa98bforg.highwire.dtl.DTLVardef@422e5borg.highwire.dtl.DTLVardef@f18187_HPS_FORMAT_FIGEXP M_FIG C_FIG