Diversity and Mechanism of Hydrogen Peroxide Transport Across MIP Channels

CHEVRIAU, JONATHAN; BUSSOLINI LIZUNDIA, ROCIO; ZEIDA, ARI; ZERBETTO DE PALMA, GERARDO; RAMOA, URSULA; ALLEVA, KARINA; CANESSA FORTUNA, AGUSTINA; VITALI, VICTORIA ANDREA

Workshop; Workshop on Redox Nutrition and Toxicology, Redox BA; 2023

Hydrogen peroxide (H2O2) is a fundamental second messenger and the study of its difussion through membranes, in and between cells, has received an impulse when it was clarified that it involves channels belonging to the MIP (membrane intrinsic protein) family. Some MIPs channels are known as aquaporins (AQP), due to its capacity to permeate water, but this family also includes channels that permeate H2O2, known as peroxiporins. The physicochemical properties of H2O2 and H2O are remarkably similar and have led to the proposition that all AQP should be a peroxiporin. However, experimental evidence doesn’t show this dual aspect for all MIPs questioning the idea of mimicry. In this work, we employ sequence similarity networks (SSN) and atomistic molecular dynamics simulations (MD) to understand the diversification of H2O2 transport through the MIP family and to unravel the transport mechanics of H2O2 and H2O across some different MIP subfamilies representatives (plant MtPIP2;3, mammalian HsAQP8 and kinetoplastid TcAQPalfa). The SSN of the MIP superfamily was generated using the EFI-EST server with UniProt information. For MD, homotetrameric channel models were created with Swiss-Model or AlphaFold and embedded in a POPC bilayer, H2O2 was incorporated to the system and simulations ran for up to 1µs. Preliminary results revealed: i- presence of peroxiporins in different MIP clusters and ii- H2O2 crossing the channel pore alongside H2O molecules with similar dipole rotation within the channel's middle section but distinct interaction patterns for H2O2 and H2O with pore-lining residues. Notably, in plant MIP channels, pH gating mechanisms controlling water permeation also regulate H2O2 transport. These findings have implications for the understanding of controlled transport of H2O2, ultimately contributing to our comprehension of critical cellular processes.