A Dissipation-Driven Mechanism for Accelerated Protein Folding Kinetics

The remarkable speed of protein folding, guided by funnel-like energy landscapes, remains a subject of intense investigation. We propose a mechanism whereby the kinetics are actively acceleratedby conformation-dependent energy dissipation. This ”hot search, cold trap” model posits that thedisordered unfolded state is inefficiently coupled to the solvent, leading to a higher effective temperature that promotes rapid exploration of the conformational space. Conversely, the ordered nativestate acts as an efficient dissipative sink, suppressing thermal fluctuations and kinetically trappingthe protein upon folding. We test this hypothesis using Langevin dynamics simulations on a 1Ddouble-well potential. Incorporating a conformation-dependent effective temperature yields a 2.85-fold acceleration in folding rates compared to a constant-temperature control. We demonstrate thatthis kinetic advantage is robust, persisting with a more physically realistic continuous temperatureprofile (2.82-fold speedup), when a state-dependent friction is included (1.37-fold speedup), andis shown to be essential for folding on a 2D rugged landscape containing non-native traps. Thisframework establishes dissipation dynamics as a key determinant of folding speed and offers a newclass of testable predictions connecting macroscopic kinetics to the microscopic physics of solventcoupling.