Linking Residue-Level Network Dynamics to Peptide Aggregate Stability: A Hierarchical Spectral Graph Analysis of KYFIL Self-Assembly

Abstract: Understanding the relationship between microscopic interactions and macroscopic stability is crucial for designing self-assembling peptide materials. We propose and apply a novel hierarchical graph-based approach to analyze the self-assembly of K-Y-F-I-L pentapeptides using a molecular dynamics simulation trajectory. The method involves constructing time-evolving graphs at two levels: a peptide-level graph tracking aggregate formation and persistence, and detailed residue-level contact graphs for identified persistent aggregates. We analyze spectral properties, such as algebraic connectivity (Fiedler value $\lambda_2$), and other graph metrics including density and clustering coefficient, focusing on their time evolution within these residue-level networks. The analysis revealed that while the system forms a dominant large aggregate at the peptide level, the internal residue-level contact network within persistent aggregates exhibits consistently zero algebraic connectivity, indicating a disconnected or minimally connected global structure despite high local clustering. This finding suggests that aggregate stability in this system may arise from a collection of dynamic local interactions rather than a single, globally robust residue network, and consequently limits the direct use of global connectivity metrics like $\lambda_2$ for predicting instability. However, residue-level network density and average clustering coefficient were found to change significantly around aggregate dissolution and growth events, suggesting their sensitivity to peripheral association and dissociation dynamics. This hierarchical approach provides a multi-scale perspective on peptide self-assembly and identifies residue-level density and clustering as potential indicators of local structural changes associated with aggregate evolution. \

Subjects:	q-bio.BM; physics.chem-ph
Cite as:	PX:2508.00031