Predicting reverse-bound peptide conformations in MHC Class II with PANDORA.

Area of Science:

• Immunology
• Computational Biology
• Structural Biology

Background:

• Recent findings show peptides binding to Major Histocompatibility Complex (MHC) class II molecules can adopt a reverse orientation.
• This reverse binding orientation still allows for effective CD4+ T cell activation, challenging existing models of immune recognition.

Purpose of the Study:

• To introduce an updated version of the PANDORA software capable of modeling peptides bound in a reversed orientation to MHC molecules.
• To address the challenge of limited structural data for reversed peptide-MHC complexes.

Main Methods:

• PANDORA utilizes integrative modeling with algorithmically reversed peptides as templates to predict reversed-bound peptide structures.
• The updated PANDORA feature was validated through two experimental studies.

Main Results:

• The new PANDORA feature achieved an average backbone binding-core L-RMSD of 0.63 Å, demonstrating high accuracy.
• Low RMSD values were maintained even when using templates from different MHC alleles and peptide sequences, indicating robustness.

Conclusions:

• The updated PANDORA software is the first tool able to model reversed-bound peptides in MHC class II molecules.
• This advancement is expected to be a valuable resource for the immunology community, supporting the development of targeted immunotherapies and novel vaccine designs.