Figure 3.

PROTAC linker length changes ΔΔG through modulating the effective strength of PPIs. The top three schematics illustrate the scenarios where a PROTAC linker is (a) too short to enable favorable contacts between the target (blue) and the E3 (green), (b) at an optimal length, and (c) sufficiently long but less frequently in a configuration that induces weak favorable PPIs (red dots). The ΔΔG trends over PROTAC linker lengths are calculated for two target-E3 pairs, (d) BTK-CRBN and (e) BRD4^BD2-VHL, under varying strengths of nonspecific attractions between proteins. The solid lines represent the baseline ΔΔG trends where only volume exclusion is modeled between the two proteins, and the dotted lines show the trends where nonspecific attractions are added. The strengths (ϵ_LJ) of attractions are indicated by different colors. Higher ϵ_LJ represents stronger attractions, and the baselines can also be considered as results at ϵ_LJ = 0. Results at ϵ_LJ = 0.125 and 0.2 kT are plotted for BTK-CRBN and results at ϵ_LJ = 0.125, 0.15, 0.175, 0.2, and 0.25 kT are plotted for BRD4^BD2-VHL. All calculations shown are obtained using MBAR, and results using TI and BAR are superimposed in Figure S5.