Multiple-Allele MHC Class II Epitope Engineering by a Molecular Dynamics-Based Evolution Protocol.

Area of Science:

• Immunology
• Computational Biology
• Vaccine Development

Background:

• Major Histocompatibility Complex class II (MHC II) alleles present peptides to T cells, crucial for immune responses.
• Developing universal binders for all human MHC II alleles is critical for effective vaccines and cancer immunotherapies.
• Existing methods struggle to create epitopes with broad binding across diverse MHC II allele repertoires.

Purpose of the Study:

• To engineer novel epitopes with simultaneous binding capabilities to all human MHC II alleles.
• To develop and validate a computational protocol for optimizing epitope-MHC II interactions.
• To enhance a *Plasmodium vivax* epitope for broad-spectrum MHC II binding and assess its immunogenicity.

Main Methods:

• Developed the PanMHC-PARCE protocol, integrating unsupervised sequence optimization via single-point mutations.
• Utilized parallel explicit-solvent molecular dynamics simulations to model MHC II-epitope complex dynamics.
• Employed scoring functions to evaluate and select mutations that improve affinity and reduce allele-specific binding gaps.

Main Results:

• Four engineered peptides demonstrated enhanced binding affinity to multiple human MHC II alleles.
• In vitro rate-binding assays confirmed improved binding characteristics of the designed peptides.
• Immunization studies in mice elicited a significant interferon-gamma cellular immune response.

Conclusions:

• The PanMHC-PARCE method successfully engineers peptides with broad and improved MHC II binding properties.
• This approach facilitates the development of next-generation vaccines and cancer immunotherapies targeting diverse populations.
• The engineered peptides show potential for eliciting robust cellular immune responses.