Chain length and amino acid composition dependence of coil-globule transition in intrinsically disordered proteins

A fundamental question related to intrinsically disordered proteins (IDPs) is whether they undergo a coil-to-globule transition with changes in cosolvent conditions. IDPs are hetero-polymers and finite in size. The chain length and amino acid composition could lead to the varying extent of compaction in IDPs and the coil-to-globule transition (theta condition). To probe the theta condition in polypeptides, we studied the behavior of polyleucine and polyglutamine with six different chain lengths (N = 16 to 512) in various concentrations (0 to 8 M) of Urea (denaturant) and TMAO (osmolyte) using coarse-grained models and computer simulations. The Flory scaling exponent of polyleucine (polyglutamine) undergoes a transition from approximately 0.6 (0.6) to 0.3 (0.5) with increasing N in water. We observed that the theta condition for both the IDPs strongly depends on N and varies as N−0.5. Depending on N, polyglutamine (polyleucine) chains reach the theta condition at different [TMAO] ([TMAO] or [Urea]), confirming that in addition to chain length, the amino acid composition also influences the theta solvent condition for the IDPs. Moreover, the theta point for smaller chain lengths (N = 16 to 64) calculated using the structure factor mimicking the small-angle X-ray scattering (SAXS) experiments and using pair distances mimicking fluorescence resonance energy transfer (FRET) experiments are in disagreement. The theta condition computed using the structure factor and pair distances converge to the same point only at large N. As the theta condition is correlated with the critical condition of liquid-liquid phase separation (LLPS) for IDPs, we predict that LLPS propensity of IDPs will increase with N.