Dose–Response Alignment Does Not Inherently Enhance Information Transmission in Signaling Pathways

Understanding how signaling pathways reliably transmit information is fundamental to explaining cellular decision-making. Several studies have suggested that Dose-Response Alignment (DoRA) --the overlapping of dose-response curves between receptor occupancy and downstream responses-- enhances information transmission by ensuring a linear mapping between occupancy and response. Here, we challenge this intuition using analytical and numerical analyses of a basic signaling mechanism. Our results show that DoRA, linearity and information transmission are fundamentally dissociable properties. We find that occupancy-response linearity is normalization-independent, whereas the measured degree of alignment depends on the normalization scheme used to compare dose-response curves. Specifically, normalization by maximal attained responses preferentially reflects occupancy-response linearity, whereas normalization by total response capacity preserves response dynamic range. Accordingly, under the first normalization, perfect alignment reflects linear occupancy-response mappings, whereas under the second normalization alignment can remain imperfect because it does not exclusively reflect linearity. Importantly, neither perfect alignment nor linearity necessarily maximize information transmission; instead, information transmission can increase through larger dynamic range or reduced noise. Our results show that efficient information transmission cannot be inferred from dose-response alignment or linearity alone, but emerges from the balance between dynamic range, biochemical noise, and input-output mapping.