Abstract:
Grasping the local structural features responsible for protein stability is essential for engineering robust biomolecules for industrial and therapeutic use. The presence of “cliques” groups of amino acids in close proximity in 6 and 7 alpha-helical bundles is being exploited here to reveal factors behind their intrinsic stability. Using a new hierarchical tree data structure representing a 3D structural prefix tree, millions of such motifs were indexed and queried in milliseconds to identify conserved local packing.
The study examines the association of the clique’s “residue depth” (distance from the molecular surface) with structural conservation across species. Through the comparison of datasets from mesophilic, thermophilic, and hyperthermophilic bacteria, the study identifies specific deeply buried cliques with putative capacity of structural anchoring. The core of the protein contains an abundant presence of highly conserved motifs. Moreover, mutations in hyperthermophilic variants display a high density of packing. Subsequently, packing density is the primary adaptation strategy to withstand more than 80°C.
The quantitation here will facilitate the rational design of proteins that can be used to increase the thermostability of enzymes. Additionally, the tree-based indexing system developed in this study allows a topology-independent framework for large-scale structural motif discovery and functional binding site identification in contemporary bioinformatics.
