Integral trans-membrane proteins are involved in different major cellular functions including e.g. cell homeostasis, cell bioenergetics and cell detoxification. Therefore their dysfunction is associated with serious human pathologies such as neurodegenerative diseases, cancer and virus infections. International consortia pursue approaches based on structural biology, cell biology and biophysics to understand the function of membrane proteins at the molecular level. Goals generally include the determination of the structure-function relationship for the proteins and also the effect of protein-lipid interactions, but often ignore the effects related to physical properties of membranes. Membrane physicists, including Partners 1 and 3, have brought evidence of the intrinsic interplay between protein shape and the properties of its membrane environment. These experiments have been limited to proteins with fixed shape and have not yet considered the role of the dynamic structural changes associated to their function. The challenge is now to investigate the feedback between the functional conformational dynamics of the protein and the physical properties of its surrounding membrane, at short and long distances. We will tackle the following, and still largely open, questions: (i) How does the conformational dynamics depend on membrane lipid composition? ii) How is it modified by the tension and curvature of the membrane? (iii) How does the conformational dynamics of the protein influence its membrane properties, such as its mobility and curvature-dependent distribution. We address these questions with proteins exhibiting large conformational changes during their ATP-ase cycle reconstituted in model membrane systems (small and giant vesicles) with controlled physico-chemical properties. This is the case of MultiDrug Resistance ABC transporters for which conformational changes associated with ATP hydrolysis are the key events of the drugs' transport. These proteins are involved in drug detoxification and protection of tissues from xenobiotics, including administered therapeutic drugs. Their structure and function are especially sensitive to the properties and composition of the surrounding membrane. We have chosen 2 ABC transporters: BmrA, a bacterial ABC from B. subtilis, fairly homologous to P-gp, and human P-gp. Tools and concepts of membrane physics can tackle from a different angle current challenges on drug transport, which is required to design new strategies of regulation and inhibition: i) dynamics and stochastic transitions between catalytic conformations of ABCs, ii) the interdependence between membrane properties and conformational dynamics iii) the role of the non-equilibrium conformational changes due to ATP hydrolysis in the lateral mobility of the proteins and in their lateral distribution. The general knowledge obtained for BmrA will be extended to investigate for the human P-gp the challenging issues of its flexibility and spatial organization during its catalytic cycle. We will combine the efforts of four groups with a unique set of expertise in structural biology, coarse-grained simulations, biomimetic systems, membrane biophysics, single-molecule biophysics and statistical physics. Thanks to a comprehensive multi-scale approach combining cryo-EM and biophysical techniques with coarse-grained simulations and theoretical models, we will be able to investigate: the shape of the ABC//membrane systems at high (with cryo-EM) or low (with CG simulations) protein density, the dynamics of the conformational changes (with single-molecule FRET measurements) and its coupling to the properties of the membrane (using micromanipulation techniques, single particle tracking and physical modeling). Overall, it will allow a novel understanding of membrane protein catalytic cycles that goes beyond the structure-function description and includes the reciprocal action between the protein and its surrounding membrane environment.