Thermodynamic principles govern evolutionary tradeoffs by regulating allostery

Allostery governs biological activities by signaling environmental cues at distal sites, however, the molecular basis for the orchestration and evolution of the second secret of life is evanescent. Seminal work sheds light embracing structure- and function-centric approaches, overlooking the widely accepted ensemble allosteric model based on a proteins free-energy landscape and the thermodynamic nature of allostery. Here, we unraveled allosteric regulation and its evolvability by examining energetic funnels of proteins harboring a highly evolvable ancient scaffold. We uncover intricate allosteric connectivities and their coordinated cross-talk to enable the statistical thermodynamic coupling. We decipher universal molecular determinants for the emergence of functions and environmental adaptability. Our integrative biophysical/statistical/evolutionary analysis ties the evolutionary forces via thermodynamic principles and decrypts how tradeoffs are settled at the molecular level.