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Baidya, L.

Publications and source records attributed to Baidya, L..

2 recordsLinked to original sources
bioRxiv2022

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

biophysics↗
bioRxiv2022

Salt Induced Transitions in the Conformational Ensembles of Intrinsically Disordered Proteins

Salts modulate the behavior of intrinsically disordered proteins (IDPs). In low ionic strength solutions, IDP conformations are primarily perturbed by the screening of electrostatic interactions, independent of the identity of the salt. In this regime, insight into the IDP behavior can be obtained using the theory for salt-induced transitions in charged polymers. However, in high ionic strength solutions, salt-specific interactions with the charged and uncharged residues, known as the Hofmeister effect, influence IDP behavior. There is a lack of reliable theoretical models in high salt concentration regimes to predict the salt effect on IDPs. Using a coarse-grained simulation model for the IDPs and experimentally measured water to salt solution transfer free-energies of various chemical groups, we studied the salt-specific transitions induced in the IDPs conformational ensemble. We probed the effect of three different salts, ranging from protective osmolyte to denaturant, on five IDPs belonging to various polymer classes classified based on charge content. The transitions observed in the IDP conformational ensembles are dependent on the salt used and the IDP polymer class. An important implication of these results is that a suitable salt can be identified to induce condensation of an IDP through liquid-liquid phase separation.

biophysics↗