Interpreting transient interactions in intrinsically disordered proteins.

Abstract

The flexible nature of intrinsically disordered proteins (IDPs) leads to a conformational ensemble with a diverse set of conformations. The simplest way to describe this ensemble is through a homopolymer model without any specific interactions. However, there has been growing evidence that the structural properties of IDPs and their relevant functions can be affected by transient interactions between specific and even non-local pairs of amino acids. Interpreting these interactions from experimental methods, each of which is sensitive to a different distance regime referred to as probing length, remains a challenging and unsolved problem. Here, we first show that transient interactions can be realized between short fragments of charged amino acids by generating conformational ensembles using model disordered peptides and coarse-grained simulations. Using these ensembles, we investigate how sensitive different types of experimental measurements are to the presence of transient interactions. We find methods with shorter probing lengths to be more sensitive, but further show that least two experimental methods with different probing lengths must be utilized to resolve both transient interactions between specific amino acids and weak interactions along the sequence. Finally, we develop an adjusted polymer model with an additional short-distance peak which can robustly reproduce the distance distribution function from two experimental measurements with complementary short and long-range probing lengths. This new model can suggest whether a homopolymer model is insufficient for a specific IDP, and quantitatively identify specific transient interactions from a background of nonspecific weak interactions.