Neither in block 1 nor in block 2:

• 2e: may be an egress channel, mouth opening on cytosol, apparait at CV*min* ~5.5 Å (narrow), exists in all structures in the three conformations, does not contain a molecule.

**Figure 8.** Summary of the four channels of CYP3A4. The heme is shown at the bottom of the channels. The F-F' loop is in green. The progesterone molecule (in purple) lies in a surface pocket (see also Figure 4 in [57]). The dashed line separates blocks 1 and 2.

**Table 1.** The four channels of CYP3A4 and its conformational states (C, O1, O2). The first channel appears at CV*lim* and the next channels appear at CV < CV*lim*. *<sup>a</sup>* Critical thickness of the ligand in Å computed as in [57]. When there are two ligands, two CV values are reported. *<sup>b</sup>* Cf: conformation (C, O1, O2), according to the authors of [60,69]. *<sup>c</sup>* See Section 2. *<sup>d</sup>* Third channel and eventually fourth channel. For 4K9U, the same CV was observed for the third and the fourth channels. *<sup>e</sup>* Ritonavir analog: see [79]. *<sup>f</sup>* Other ritonavir analog: see [95]. *<sup>g</sup>* The topology is constituted by several MCPs having common parts (see Section 2.2).


**Table 2.** Location of the four major access channels of CYP3A4. *<sup>a</sup>* According to the authors of [60,69]: C (closed conformation), O1 (conformation opened, in block 1), O2 (conformation opened, in block 2; opening of O2 is larger than opening of O1). *<sup>b</sup>* The triangulations of the channels performed with CCCPP can be described with lengthy technical details that we consider to be non essential in this paper, such as the lining atoms and residues: see these latter in Table 3.10 in [69]. *<sup>c</sup>* Substrate recognition sites (SRS), according to the authors of [70]. *<sup>d</sup>* Depending on the ligand size, channel 2f can offer a larger opening than channel 2a.

