Struct Dyn. 2025 Nov 24;12(6):064101. doi: 10.1063/4.0000781. eCollection 2025 Nov.
ABSTRACT
Given proteins’ fundamental importance in human health and catalysis, the relationships between protein sequence, structure, dynamics, and function have become a topic of great interest. One way to extract information from proteins is to compute the local energetic frustration of their native state. Traditionally, energetic frustration calculations require protein structures as a starting point. However, using a single protein structure to evaluate the energetic frustration for a given amino acid sequence does not always fully represent the protein’s structural ensemble. Therefore, we have developed a sequence-based method to evaluate energetic frustration in proteins using direct coupling analysis and statistical potentials. Our approach exhibits significant agreement with established structure-based frustration methods in terms of their mutual agreement with crystallographic B-factor. Moreover, our sequence-based method shows elevated precision in classifying high B-factor residues, suggesting that it has some robustness to unstructured regions of proteins.
PMID:41312536 | PMC:PMC12657058 | DOI:10.1063/4.0000781
