A thermodynamic framework for mapping elastic recoil mechanism across the human proteome

Abstract

The folding thermodynamics of proteins are dominated by two opposing forces, the loss in backbone entropy and the packing of hydrophobic groups. The same forces are major contributors to the extension thermodynamics of elastic proteins with the distinction that both processes act in concert, favoring the higher chain and solvent entropy of a relaxed conformation. The relative entropic contributions specify the recoil mechanism; human elastin recoil is primarily driven by hydrophobic forces, whereas fly resilin has a rubber-like mechanism driven by backbone entropy. Despite the importance of elastic proteins to tissue biomechanics, few have been identified, let alone characterized to the same extent as elastin and resilin. We develop a thermodynamic framework that maps proteins by sequence-derived estimates of extension-induced backbone and solvent entropy changes. Putative elastic proteins are proposed and classified by recoil mechanism based on estimated thermodynamic features. Proteins that map to elastic regions are overrepresented by the skin proteome. The set of predicted elastic domains is further extended by incorporating sequence context embedded in protein language models. Protein domains with distinct thermodynamic recoil mechanisms cluster on the latent space manifold. Some of these domains are anticipated to have roles within molecular machines, expanding the scope of elastic protein function beyond mechanical materials like elastin and resilin. SIGNIFICANCE STATEMENT Elastic proteins enable tissues and molecular assemblies to store and recover mechanical energy, yet only a handful, such as elastin and resilin, have been characterized in detail. We introduce a sequence-derived thermodynamic framework that maps proteins according to the relative contributions of backbone conformational entropy and solvent entropy to elastic recoil. Applied to the human proteome, this approach identifies numerous candidate elastic proteins and domains enriched in skin, extracellular matrix, cytoskeletal, and macromolecular assembly functions. Integration with protein language models further reveals that proteins sharing similar recoil mechanisms form distinct neighborhoods in latent space despite limited sequence homology. These findings suggest that elastic function is far more widespread than currently recognized and provide a general strategy for discovering and mechanistically classifying elastic proteins across biological systems.