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Toward Accurate Simulation of Coupling between Protein Secondary Structure and Phase Separation
Yumeng Zhang1, Shanlong Li1, Xiping Gong1
1Department of Chemistry, University of Massachusetts, Amherst, Massachusetts 01003, United States.
Journal of the American Chemical Society
|December 19, 2023
Summary
A new hybrid resolution (HyRes) protein model accurately simulates intrinsically disordered protein (IDP) phase separation, capturing backbone and secondary structure effects crucial for biomolecular condensate formation.
Area of Science:
- Biophysics
- Computational Biology
- Protein Science
Background:
- Intrinsically disordered proteins (IDPs) drive biomolecular condensate formation via phase separation.
- Coarse-grained (CG) simulations are vital for studying IDP phase separation.
- Current Cα-only models lack accuracy in representing peptide backbone interactions and secondary structures.
Purpose of the Study:
- Introduce a hybrid resolution (HyRes) protein model for enhanced accuracy in IDP phase separation simulations.
- Evaluate HyRes's ability to capture backbone-mediated interactions and transient secondary structures.
- Assess HyRes's efficiency and accuracy in simulating spontaneous phase separation and mutant effects.
Main Methods:
- Developed a hybrid resolution (HyRes) model with an atomistic backbone and coarse-grained side chains.
- Simulated spontaneous phase separation of the GY-23 protein using HyRes.
- Investigated the impact of single amino acid mutations (His to Lys) on phase separation.
- Analyzed phase separation of TDP-43 using HyRes, focusing on disease-related mutants in the conserved region (CR).
Main Results:
- HyRes accurately models monomeric IDP helical propensity and chain dimensions.
- Simulations successfully captured spontaneous phase separation and mutation effects for GY-23.
- HyRes predicted increased β-structure formation in condensates, aligning with experimental data.
- HyRes simulations recapitulated the effects of TDP-43 CR mutants on helicity and phase separation propensity.
- Analysis indicated that the balance of backbone and side chain interactions, not helicity alone, dictates phase separation.
Conclusions:
- HyRes is an effective protein model for simulating IDP phase separation.
- The model accurately captures the influence of transient secondary structures on phase separation.
- HyRes facilitates a deeper understanding of the interplay between protein structure and phase separation phenomena.
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