Calibrated Langevin dynamics simulations of intrinsically disordered proteins

TL;DR

This study develops a calibrated coarse-grained Langevin dynamics model for intrinsically disordered proteins, accurately capturing their conformational behavior and scaling properties across multiple IDPs using experimental data.

Contribution

The paper introduces a robust, calibrated CG model that reproduces IDP conformations and scaling behavior, validated against extensive experimental FRET data.

Findings

The model accurately predicts inter-residue separations across diverse IDPs.

There is a strong correlation between charge/hydrophobicity and the scaling exponent.

The model is robust to different hydrophobicity scales.

Abstract

We perform extensive coarse-grained (CG) Langevin dynamics simulations of intrinsically disordered proteins (IDPs), which possess fluctuating conformational statistics between that for excluded volume random walks and collapsed globules. Our CG model includes repulsive steric, attractive hydrophobic, and electrostatic interactions between residues and is calibrated to a large collection of single-molecule fluorescence resonance energy transfer data on the inter-residue separations for 36 pairs of residues in five IDPs: $\alpha$-, $\beta$-, and $\gamma$-synuclein, the microtubule-associated protein $\tau$, and prothymosin $\alpha$. We find that our CG model is able to recapitulate the average inter-residue separations regardless of the choice of the hydrophobicity scale, which shows that our calibrated model can robustly capture the conformational dynamics of IDPs. We then employ our model to study the scaling of the radius of gyration with chemical distance in 11 known IDPs. We identify a strong correlation between the distance to the dividing line between folded proteins and IDPs in the mean charge and hydrophobicity space and the scaling exponent of the radius of gyration with chemical distance along the protein.