Heat dissipation guides activation in signaling proteins

Jeffrey K. Weber, Diwakar Shukla, Vijay S. Pande

Research output: Contribution to journalArticlepeer-review


Life is fundamentally a nonequilibrium phenomenon. At the expense of dissipated energy, living things perform irreversible processes that allow them to propagate and reproduce. Within cells, evolution has designed nanoscale machines to do meaningful work with energy harnessed from a continuous flux of heat and particles. As dictated by the Second Law of Thermodynamics and its fluctuation theorem corollaries, irreversibility in nonequilibrium processes can be quantified in terms of how much entropy such dynamics produce. In this work, we seek to address a fundamental question linking biology and nonequilibrium physics: can the evolved dissipative pathways that facilitate biomolecular function be identified by their extent of entropy production in general relaxation processes? We here synthesize massive molecular dynamics simulations, Markov state models (MSMs), and nonequilibrium statistical mechanical theory to probe dissipation in two key classes of signaling proteins: kinases and G-protein-coupled receptors (GPCRs). Applying machinery from large deviation theory, we use MSMs constructed from protein simulations to generate dynamics conforming to positive levels of entropy production. We note the emergence of an array of peaks in the dynamical response (transient analogs of phase transitions) that draw the proteins between distinct levels of dissipation, and we see that the binding of ATP and agonist molecules modifies the observed dissipative landscapes. Overall, we find that dissipation is tightly coupled to activation in these signaling systems: dominant entropy-producing trajectories become localized near important barriers along known biological activation pathways. We go on to classify an array of equilibrium and nonequilibrium molecular switches that harmonize to promote functional dynamics.

Original languageEnglish (US)
Pages (from-to)10377-10382
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number33
StatePublished - Aug 18 2015
Externally publishedYes


  • Entropy production
  • Functional dynamics
  • Heat dissipation
  • Markov state models
  • Signaling proteins

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Heat dissipation guides activation in signaling proteins'. Together they form a unique fingerprint.

Cite this