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This study introduces a bench-compatible method to experimentally manipulate local molecular structure as a variable in chemical assays, challenging the traditional reliance on molarity as a singular readout. It reveals that in structured environments, the shape of the target's local space can significantly influence chemical binding responses, independent of concentration. The findings highlight a critical oversight in macroscopic assays, demonstrating that preserving geometric information can enhance the understanding of molecular interactions in complex environments.
In structured environments, the shape of the target can dictate chemical binding strength, rendering traditional concentration metrics insufficient.
Chemical kinetics has long inferred local molecular behaviour through the flask-and-molarity pairing, where well-mixed concentrations serve as the experimental readout. Yet many biological reactions occur in structured environments. Researchers have long recognized that concentration may not carry the same operational meaning in such environments, but even local concepts such as effective molarity usually translate local effects back into a single value with units of concentration. What has been missing is the complementary path: a bench-compatible way to make local structure an experimental variable, rather than only a correction to molarity. Here we show a chemistry-geometry crossover that the flask-and-molarity interface could not make visible. In the micromolar-or-weaker affinity regime, inhibition can switch sharply out of the familiar concentration-and-affinity mode: chemical binding strength no longer determines the response, and the shape of the target's local space does. A bench-compatible interface made this switch measurable by separating bulk dose from local geometry. This blind spot arose from the hidden premise that macroscopic pooling makes a structured local state readable as a single local concentration. The chemistry-geometry crossover breaks that premise: in a structured target environment, a macroscopic assay can remain sensitive to the probability distribution of local states, so collapsing that distribution to one concentration-valued number removes the geometric control axis from the readout. By preserving that axis in the experiment, the interface bypasses molarity's hidden bottleneck and provides a routine experimental route to remeasure and reinterpret molecular interactions in structured space.