Prediction of amphipathic helix-membrane interactions with Rosetta

Area of Science:

• Biophysics
• Computational Biology
• Structural Biology

Background:

• Amphipathic helices are crucial for membrane protein function and stability.
• Existing computational tools lack specific capabilities for modeling amphipathic helix-membrane interactions within the Rosetta software suite.

Purpose of the Study:

• To develop and validate a computational protocol, AmphiScan, for modeling amphipathic helix interactions with membranes using PyRosetta.
• To provide a tool for predicting the orientation and membrane-embedding of amphipathic helices.

Main Methods:

• Developed the AmphiScan protocol utilizing PyRosetta for grid-based conformational searching.
• Benchmarked AmphiScan against established membrane modeling tools and score functions (RosettaMembrane, ref2015_memb, franklin2019).
• Validated performance using diverse datasets of engineered and natural amphipathic helices and various membrane coordinate sources.

Main Results:

• AmphiScan accurately predicted amphipathic helix coordinates within 3Å of reference structures.
• The protocol achieved a Matthews Correlation Constant (MCC) of up to 0.57 in identifying membrane-embedded residues.
• Demonstrated high accuracy and speed across multiple benchmark datasets and scoring functions.

Conclusions:

• AmphiScan is a fast, accurate, and customizable protocol for modeling amphipathic helix-membrane interactions.
• The tool addresses a significant gap in computational modeling capabilities within the Rosetta framework.
• AmphiScan can be integrated into broader computational pipelines for enhanced protein-membrane studies.