A. Interactions of UraA with the POPE, POPG and CL molecules as a function of the simulation time for one of the CG simulations with the wild type UraA (10 us simulation; UraA-CG in Table 1).

Number of CL (A), POPG (B) and POPE (C) lipids in contact with the UraA over the course of the simulations with the wild type and the mutated forms of UraA.

On average, UraA associates with ~ 2 or 3 CLs, ~ 8 POPGs and ~ 12 POPEs in the simulations with the wild type protein.

Acute transverse hippocampal slices (400 um) were prepared as previously described [42,52—54] from 19—25 days-old wild type mice.

Because Kir4.1'/' mice display altered synaptic plasticity compared to wild type mice [22,26] , we recalibrated the synaptic current (lapp) parameters TreC and Tinact in equations 1,2 (see Table 1) for the facilita-tion-depression model to get an optimal fit to the recorded postsynaptic responses [26].

Experiments were performed on the hippocampus of wild type mice (C57BL6).

We consider two spatial compartments with dichotomic distributions of drugs: compartment ‘0’ can hardly be penetrated by the cancer drug, thereby representing a perfect drug sanctuary site; compartment ‘1’ is distributed with an adequate amount of drugs that is able to completely wipe out any wild type cells.

We denote the genotypes of cells by the number of acquired point mutations: the wild type ‘0’ and the resistant type ‘1’ (see Materials & Methods for a detailed description of the model).

Moreover, the fitness cost of resistance, 5, for resistant cells located in the sanctuary compartment 0 can be parameterized as 1910 = (1—5)b00, while the fitness cost of sensitivity, 6, for wild type cells in the drug-containing compartment 1, 1901 = (1—6)b00.