Studies on the human Pgp folding

Overexpression of P-glycoprotein (Pgp/ABCB1) in cancer is a marker of overall poor chemotherapy response and prognosis. This computational project builds on previous studies lead by the PI and Co-PI on multidrug resistance (MDR) in cancer by using computational models and simulations for gaining information about the inner dynamics, structural features and drug-Pgp interaction and mode of action.

The human Pgp conformations deposited recently on the Protein Data Bank revealed a new inward facing conformation that may represent either the closing of a gate region or an artifact derived from lateral compression in a too small size nanodisc, used to stabilize the transporter. Using a simpler model, we have done preliminary investigations pointing for the presence of an artifact in the experimental protocol (DOI:10.1101/692988).

However, this hypothesis can only be tested and settled using molecular dynamics simulations at very long time scales with complete atomistic description of the biochemical system, impossible to match using in-house resources. Knowing if there is an artifact on the human structures or if this new structures correspond to a yet to be confirmed meta-stable intermediary state is of capital importance since further computational studies of Pgp can only produce reliable information when using Pgp structures representative of its correct native fold.