Modulating Charge Patterning and Ionic Strength as a Strategy to induce Conformational Changes in Intrinsically Disordered Proteins

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College of Natual Science and Mathematics, Physics and Astronomy


Conformational dynamics, Electrostatics, Polyelectrolytes, Phosphorylation, Proteins, Post-translational modifications, Polymers


We present an analytical theory to describe conformational changes as a function of salt for polymers with a given sequence of charges. We apply this model to describe Intrinsically Disordered Proteins (IDPs) by explicitly accounting for charged residues and their exact placement in the primary sequence while approximating the effect of non-electrostatic interactions at a mean-field level by effective short-range (two body and three-body) interaction parameters. The effect of ions is introduced by treating electrostatic interactions within Debye-Huckle approximation. Using typical values of the short-range mean-field parameters derived from all-atom Monte Carlo simulations (at zero salt), we predict the conformational changes as a function of salt concentration. We notice that conformational transitions in response to changes in ionic strength strongly depend on sequence specific charge patterning. For example, globule to coil transition can be observed upon increasing salt concentration, in stark contrast to uniformly charged polyelectrolyte theories based on net charge only. In addition, it is possible to observe non-monotonic behavior with salt as well. Drastic differences in salt-induced conformational transitions is also evident between two doubly phosphorylated sequences—derived from the same wild type sequence—that only differ in the site of phosphorylation. Similar effects are also predicted between two sequences derived from the same parent sequence differing by a single site mutation where a negative charge is replaced by a positive charge. These effects are purely a result of charge decoration and can only be understood in terms of metrics based on specific placement of charges, and cannot be explained by models based on charge composition alone. Identifying sequences and hot spots within sequences—for post translational modification or charge mutation—using our high-throughput theory will yield fundamental insights into design and biological regulation mediated by phosphorylation and/or local changes in salt concentration.

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