HyRes: Accurate Physics-Based Simulation of Dynamic Protein Structures and Interactions in Complex Environments at...

Area of Science:

• Biophysics
• Computational Biology
• Structural Biology

Background:

• Intrinsically disordered proteins (IDPs) are crucial for cellular regulation but challenging to study due to their dynamic nature.
• Existing methods struggle to balance accuracy and computational efficiency for large-scale IDP analysis.

Purpose of the Study:

• To develop a physics-based, hybrid-resolution protein model (HyRes) for efficient and accurate simulation of IDP conformational ensembles.
• To assess HyRes's performance against established methods and its transferability across various biological environments.

Main Methods:

• Developed HyRes, a hybrid-resolution model with atomistic backbones and intermediate-resolution sidechains.
• Validated HyRes across ~100 IDPs, comparing results to all-atom force fields.
• Applied HyRes to generate ensembles for ~30,000 human proteome and DisProt IDPs.

Main Results:

• HyRes accurately reproduces experimental chain dimensions, transient contacts, and secondary structures of IDPs.
• The model demonstrates exceptional transferability, capturing IDP dynamics in dilute, condensed, and amyloidogenic phases.
• A strong correlation was found between residual structures and cellular function/localization in large-scale IDP analysis.

Conclusions:

• HyRes offers a computationally efficient and accurate approach for studying IDP dynamics and interactions.
• The generated database of disordered ensembles provides valuable resources for IDP biology and deep learning applications.
• HyRes facilitates a deeper understanding of the link between IDP structure, function, and cellular processes.