To further elucidate the lipid-cluster mode of interaction, a probe orientation analysis was introduced. It follows the orientation of the probe in regard to the geometric center of the involved cluster (Figure ). Similar to the dynamic HIP analysis, we calculated the shift in probe orientation (orientation shift) between modulator-rich and modulator-poor clusters (Figure , Supp. Figure ). As before, the most affected chemistries match probe-modulator pairs that experience substantial rate modifications, leading to more tangential probe orientations that suggest higher headgroup involvement.