Accurate Simulation of Coupling between Protein Secondary Structure and Liquid-Liquid Phase Separation

Area of Science:

• Computational Biology
• Biophysics
• Protein Dynamics

Background:

• Intrinsically disordered proteins (IDPs) drive liquid-liquid phase separation (LLPS), crucial for membraneless organelle formation.
• Current coarse-grained (CG) models, like Cα-only, lack accuracy in representing IDP backbone interactions and secondary structures during LLPS.
• Accurate modeling is needed to understand the sequence-specific mechanisms governing IDP phase separation.

Approach:

• Developed a hybrid resolution (HyRes) model with an atomistic backbone and coarse-grained side chains for IDP simulations.
• Validated HyRes by accurately predicting monomeric IDP properties like helical propensity and chain dimensions.
• Simulated spontaneous LLPS of GY-23 and TDP-43 using HyRes, assessing its efficiency and accuracy for single mutations and disease-related variants.

Key Points:

• HyRes efficiently simulates spontaneous LLPS and resolves single mutation effects, outperforming Cα-only models.
• Simulations predict increased β-sheet formation within condensates, aligning with experimental observations.
• HyRes accurately models disease-related mutations in TDP-43, showing their impact on helicity and LLPS propensity.

Conclusions:

• The HyRes model provides a significant advancement for molecular simulations of IDP phase separation.
• LLPS propensity is determined by the interplay of backbone and sidechain interactions, not solely helicity.
• HyRes will facilitate deeper understanding of the coupling between transient secondary structures and LLPS in IDPs.