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The European High Performance Computing Joint Undertaking (EuroHPC JU)

PROTONPUMP: The Molecular Mechanism of Stomach Acidification

Awarded Resources (in core hours)
Vega GPU
System Partition
1 November 2022 - 31 October 2023
Allocation Period

P-type ATPase ion pumps transport ions uphill against their chemical potential to maintain the transmembrane (TM) electrochemical potential in cells which powers vital biological functions such as neuronal signaling, energy transduction and stomach acidification.

We will investigate mechanisms of ion transport and selectivity in the mammalian gastric H+, K+ ATPase (HKA) which acidifies the stomach. The first goal of the project is to unravel the molecular mechanism of ion binding and release and ion selectivity of K+ over Na+ for the mammalian HKA pump.

The second goal is to decipher the mechanism of proton binding and release. We will employ conventional molecular dynamics (MD) simulations, enhanced-sampling free energy methods and a recently available highly efficient constant pH algorithm.

Our investigations will be experimentally corroborated and will have broad implications for H+ transport in many membrane proteins, particularly so because H+ transport simulations are technically challenging. The HKA is a target of some of the highest selling drugs, and remains an active pharmaceutical target.