Entropy-driven physical amplification in multivalent biosensing

Abstract

Sensitive detection of low-abundance molecular targets is widely assumed to require enzymatic amplification, such as PCR, to achieve low detection limits. In amplification-free platforms, sensitivity is traditionally constrained by equilibrium binding affinity. Here we show that multivalent linker entropy provides a distinct physical route to exponential sensitivity enhancement in purely equilibrium sensing architectures. Using a statistical-mechanical theory supported by grand canonical Monte Carlo simulations, we demonstrate that redistributing a fixed total interaction strength over increasing linker valency exponentially lowers adsorption thresholds. This scaling emerges not from stronger energetic affinity, but from the rapid growth of combinatorial binding configurations, revealing entropy as an intrinsic amplification mechanism. Consequently, detection limits can be tuned independently of bond strength, enabling ultrasensitive responses without enzymatic replication. Our results establish a general physical design principle for engineering amplification-free detection systems capable of approaching PCR-level sensitivities through entropy-driven collective effects.