Effect of Charge Distribution on the Dynamics of Polyampholytic Disordered Proteins

Abstract

The stability and physiological function of many biomolecular coacervates depend on the structure and dynamics of intrinsically disordered proteins (IDPs) that typically contain a significant fraction of charged residues. Although the effect of relative arrangement of charged residues on IDP conformation is a well-studied problem, the associated changes in dynamics are far less understood. In this work, we systematically interrogate the effects of charge distribution on the chain-level and segmental dynamics of polyampholytic IDPs in dilute solutions. We study a coarse-grained model polyampholyte consisting of an equal fraction of two oppositely charged residues (glutamic acid and lysine) that undergoes a transition from an ideal chainlike conformation for uniformly charge-patterned sequences to a semicompact conformation for highly charge-segregated sequences. Changes in the chain-level dynamics with increasing charge segregation correlate with changes in conformation. The chain-level and segmental dynamics conform to simple homopolymer models for uniformly charge-patterned sequences but deviate with increasing charge segregation, in both the presence and absence of hydrodynamic interactions. We discuss the significance of these findings, obtained for a model polyampholyte, in the context of a charge-rich intrinsically disordered region of the naturally occurring protein LAF-1. Our findings have important implications for understanding the effects of charge patterning on the dynamics of polyampholytic IDPs in dilute conditions using polymer scaling theories.

Expanding the molecular language of protein liquid-liquid phase separation

“…2c bottom ), which is in line with the current expectation that these residues act as primary drivers of LLPS 18, 19, 21, 26 . To rule out the possibility that the commonly used restrictive distance-based contact definition is overcounting contact pairs involving non-Arg/Tyr residues 32 , we estimate the energetic contribution of different contact pairs (see Methods and Ref. for details).…”

“…It is hypothesized that the overall interactions between the Arg and aromatic sidechains – including hydrogen bonding, sp 2 /π, and the electrostatic interaction between the guanidinium group and the aromatic ring – contribute to the strength of this interaction 12, 20, 21, 24 . Many studies have also highlighted the role of charge-charge attraction between oppositely charged residues (Arg/Lys with Asp/Glu) in modulating the phase behavior of different proteins 19, 24, 32 .…”

Role of Strong Localized vs Weak Distributed Interactions in Disordered Protein Phase Separation

“…For the HP+ model, we found a near perfect overlap of P ( R g ) (Figure b), implying that the single-chain conformations in the HP+ model were almost identical to those of a purely hydrophobic reference sequence for all investigated X P values. To further test this similarity, we considered the shape anisotropy ⟨κ 2 ⟩, computed using the eigenvalues of the gyration tensor; , the nonbonded potential energies U nb ; and the relaxation time τ e of the end-to-end vector autocorrelation function (Figure c). Remarkably, we found for almost all X P values ⟨κ 2 ⟩ ≈ 0.39, similar to the numerically determined value of a three-dimensional random walk, despite the very different sequence compositions.…”

“…Interactions between bonded beads were modeled using a harmonic potential, U normalb ( r ) = k normalb 2 false( r − r 0 false) 2 with distance r between monomers, spring constant k b = 2000 kcal/(mol nm 2 ) and equilibrium bond length r 0 = 0.38 nm. Nonbonded interactions were modeled using a modified Lennard–Jones potential, where the attractive contribution was scaled independently of the short-range repulsion by the pairwise hydropathy λ ij for monomers of type i and j , ,− U nb ( r ) = true{ true U LJ false( r false) + false( 1 − λ i j false) ε , r ≤ 2 1 / 6 σ λ i j U LJ false( r false) , otherwise where U LJ is the standard Lennard–Jones potential, U normalLJ ( r ) = 4 ε [ ( σ r ) 12 − ( …”

“…Interactions between bonded beads were modeled using a harmonic potential, with distance r between monomers, spring constant k b = 2000 kcal/(mol nm 2 ) and equilibrium bond length r 0 = 0.38 nm. Nonbonded interactions were modeled using a modified Lennard–Jones potential, where the attractive contribution was scaled independently of the short-range repulsion by the pairwise hydropathy λ ij for monomers of type i and j , ,− where U LJ is the standard Lennard–Jones potential, where ε is the interaction strength. We note that eq reduces to the purely repulsive Weeks–Chandler–Andersen potential, which describes excluded volume interactions between monomers under good solvent conditions, for λ ij = 0 and to eq , which also includes effective attraction between monomers as in a lower quality solvent, for λ ij = 1.…”