Studies on the human Pgp folding
Status
Past
Acronym
No Acronym
Project Reference
Start
2022-03-09
End
2023-03-08
Funding Total
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.
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.