Natively Unfolded Protein Stability as a Coil-to-Globule Transition in Charge/Hydropathy Space

Abstract

In the absence of experimental assignments, the empirical charge/hydropathy correlation for the prediction of natively unfolded protein sequences (Uversky, V. N.; Gillespie, J. R.; Fink, A. L. Proteins: Struct., Funct., Genet. 2000, 41, 415-427) provides perhaps the most intuitive description of gross polypeptide conformation. The success of this correlation rests on an essential chain length independence of the boundary line between expanded and compact conformations, conversely stabilized by highly charged/weakly hydrophobic residues or weakly charged/highly hydrophobic residues, respectively. We present extensive simulation results for coarse-grained polypeptides over a wide range of sequence hydrophobicities, charges, and lengths. A coil-to-globule transition in sequence composition space analogous to the charge/hydropathy correlation is observed. A near sequence length independent stability boundary is only found when counterions for the charged peptides are explicitly included, as a result of counterion condensation stabilization of repulsive electrostatic interactions on the globule surface. The observed counterion adsorption is shown to be in quantitative agreement with theoretical condensation predictions. We argue that alternate functionalities, beyond charge and hydrophobicity, empirically known to correlate with conformational disorder can be incorporated into our minimalist polypeptide model to study the interplay between independent predictors of unfolded sequences.

Net charge per residue modulates conformational ensembles of intrinsically disordered proteins

“…The line of Uversky et al (21) is a plane separating folded proteins from IDPs. Contrary to previous assumptions (16), the phase diagram is not featureless below this plane. Sequences with low overall hydrophobicity can either be swollen coils or compact globules and the net charge per residue determines the preferred phase.…”

“…To test the predictions made in Figs. 2-4, we studied a subset of the protamines (2,4,5,6,8,11,12,16,18, and 21) using fluorescence correlation spectroscopy (FCS) and fluorescence anisotropy. Both sets of measurements were performed using peptides labeled at their C termini with tetramethylrhodamine-5-maleimide (TMR).…”

“…Many of these interactions promote disorder-to-order transitions within IDPs (3,9), and different mechanistic models (3,12,13) have been proposed for coupled folding and binding. To develop a better understanding of how disorder is used in function (2), we have pursued quantitative, polymer-physics-based descriptions (14)(15)(16) for conformational ensembles of IDPs (17)(18)(19)(20).…”

Molecular simulations of protein disorderThis paper is one of a selection of papers published in this special issue entitled “Canadian Society of Biochemistry, Molecular & Cellular Biology 52nd Annual Meeting — Protein Folding: Principles and Diseases” and has undergone the Journal's usual peer review process.

“…Coarse-grained simulations have helped to elucidate the biophysical underpinnings of the sequence characteristics of disordered proteins uncovered by bioinformatics (Ashbaugh and Hatch 2008;Szilágyi et al 2008). For example, it is known that the compositions of IDPs and IDRs tend to be depleted in hydrophobic residues and enriched in charged residues ).…”

Assembly of multi-flavored two-dimensional colloidal crystals

“…Section 2). 44 Thus, for a binary system of “A” and “B” particles, there are three values that need to be specified: 〈λ A,A , λ A,B , λ B,B 〉. Physically, these parameters describe the cohesive interaction between like particles, λ i,i , and the adhesive interaction between unlike particles, λ i,j .…”