Researchers discovered that single amino acid changes located far from a protein's binding site can dramatically alter how drugs attach to the target, even when the protein's overall structure remains unchanged. The mutation works by shifting the protein's dynamic conformational ensemble—the collection of slightly different shapes it naturally adopts in solution. This mechanism explains how evolutionary pressure can fine-tune drug sensitivity without disrupting protein stability or primary function. The finding challenges the traditional view that mutations either break proteins or leave them unchanged, revealing instead a sophisticated middle ground where distant modifications create subtle but functionally important shifts in molecular behavior. This represents a paradigm shift for drug development, suggesting that resistance mutations don't always occur at obvious binding sites but can emerge from seemingly unrelated regions. The discovery also provides new insight into how proteins evolve—not just through dramatic structural changes, but through nuanced adjustments to their dynamic properties. For therapeutic development, this means drug designers must consider the entire protein surface as potentially relevant, not just the immediate binding pocket, when predicting resistance patterns or designing more robust pharmaceuticals.