SpiDec: Computing binodals and interfacial tension of biomolecular condensates from simulations of spinodal decomposition

Abstract

Phase separation of intrinsically disordered proteins (IDPs) is a phenomenon associated with many essential cellular processes, but a robust method to compute the binodal from molecular dynamics simulations of IDPs modeled at the all-atom level in explicit solvent is still elusive, due to the difficulty in preparing a suitable initial dense configuration and in achieving phase equilibration. Here we present SpiDec as such a method, based on spontaneous phase separation via spinodal decomposition that produces a dense slab when the system is initiated at a homogeneous, low density. After illustrating the method on four model systems, we apply SpiDec to a tetrapeptide modeled at the all-atom level and solvated in TIP3P water. The concentrations in the dense and dilute phases agree qualitatively with experimental results and point to binodals as a sensitive property for force-field parameterization. SpiDec may prove useful for the accurate determination of the phase equilibrium of IDPs.

Amino Acid-Dependent Material Properties of Tetrapeptide Condensates

“…Previously we observed spontaneous condensate formation in molecular dynamics simulations of 64 copies of FFssFF in explicit water 37 . Here we changed to a force-field combination that was found to model well IDPs in explicit water 38 and expanded the simulations to all eight tetrapeptides.…”

Adenosine Triphosphate Mediates Phase Separation of Disordered Basic Proteins by Bridging Intermolecular Interaction Networks

“…The amplitude of the corresponding trapping force and its phase shift from the oscillating bead position (Figure 6b) allow for the determination of the elastic modulus G′(ω) and viscous modulus G″(ω). We fit the frequency dependences of G′(ω) and G″(ω) to the Jeffreys model 38 (Figure 6c):…”

“…To understand the very unusual properties of bIDP-ATP droplets, we carried out all-atom explicit solvent simulations of PM-ATP condensate formation. By following spinodal decomposition of a mixture with 16 PM chains and 84 ATP molecules (resulting in charge neutralization), we were able to observe spontaneous formation of a dense slab in a cubic simulation box (Figure S9 and Movie S1), which corresponds to droplet formation in a bulk system. We then extended the simulations in a longer box; the slab is stable in the course of 900 ns of simulations (Figure a, left panel; Figure S10, first panel).…”

“…We duplicated this glob to build a system with 16 PM chains neutralized by 84 ATP molecules and solvated with 82,412 TIP4PD water molecules, in a cubic box with a side length of 140 Å. To induce the condensation of the 16 PM chains into a slab, 70% of the water molecules were removed. The resulting system was energy minimized and equilibrated as described above, except that the last stage was at constant NPT for 630 ns.…”

ATP Mediates Phase Separation of Disordered Basic Proteins by Bridging Intermolecular Interaction Networks

“…To understand the very unusual properties of bIDP-ATP droplets, we carried out all-atom explicit solvent simulations of PM-ATP condensate formation. By following spinodal decomposition 41 of a mixture with 16 PM chains and 84 ATP molecules (resulting in charge neutralization), we were able to observe spontaneous formation of a dense slab in a cubic simulation box (Fig. S7 and Supplementary Movie 1), which corresponds to droplet formation in a bulk system.…”