**Abbreviations**


#### **Appendix A**

#### **Preparation of additional models of CYP 2C9**

Four additional models of CYP 2C9 were built to investigate sensitivity of the CG simulations to the initial structures used.

**CYP 2C9 model 1**: The CYP 2C9 model was generated using the CYP 2C9 crystal structure (PDB 1R9O) as a template. For modeling the missing residues in the linker region (residues 38–42) and in the F'–G' helices region (residues 214–220), CYP 2C19 was used as a template only for these missing regions. The corresponding CG system is referred to as M1.

**CYP 2C9 model 2**: Another model of CYP 2C9 was generated using the complete 1R9O and 4GQS crystal structures as templates, which generated intermediate side chain conformations between the CYP 2C9 and CYP 2C19 structures. The corresponding CG system is referred to as M2.

**CYP 2C9 model 3**: Modeling of CYP 2C9 was also performed by using only a single template of the CYP 2C19 crystal structure (PDB 4GQS). This model of CYP 2C9 resembles CYP 2C19 in side chain conformations and the corresponding CG system is called M3.

**CYP 2C9 model 4**: Modeled structure of CYP 2C9 (residues 26–490) with the F'–G' helices taken from previous studies by Cojocaru et al. [22]. The details of the modeling procedure are given in that paper. The missing TM-helix was modeled as for the other models. The corresponding CG system is referred to as M4.
