The influence of the lipid environment on human AQP1: an in silico study

JUAN JOSÉ CASAL; DORR, RICARDO A.; TORIANO, ROXANA

Ciudad de Buenos Aires

Congreso; Congreso anual de la sociedad Argentina de Fisiología (SAFIS); 2021

Argentinean Physiological Society and the Latin American Association of Physiological Sciences

Introduction. The water channels (aquaporins) can transit from a state of high-water permeability to a closed state. We study the influence of the lipid environment on human Aquaporin-1 (hAQP1, PDB code: 4CSK) with molecular dynamics simulations (MDS). Two heterogeneous lipid bilayers, representative of mammals (M) and cancer cells (C), and other only 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), were generated around 4CSK.Methods. CHARMM-GUI was used for the generation of the three systems. 4CSK was embedded into 70 × 70 Å lipid bilayers, with TIP3P water molecule model, neutralizing ions, and a temperature set at 37ºC. The CHARMM36m force field was used at dynamics of 100 ns. GROMACS and VMD were used to evaluate RMSD (stability of the simulation), membrane density, profile of the pore, electronic density, molecule diffusion, distances between selectivity residues (ar/R) and the number of water molecules near them, pore length in the narrow zone, and protein flexibility (capturing the local bending angle of alpha helices). Comparative mean, SD and ANOVA test was used in statistics.Results. Constriction in the ar/R site: varied from a narrow to a wide conformation. A closed state coincides with the absence of water molecules at the site. Membrane electron density: differences among M and C systems. Diffusion of protein in DPPC: 1.390 (4.5 10-3) > M: 0.853 (5.9 10-3) > C: 3.528 (1.7 10-2), units: 10-9 cm2s-1. Pore length: longer in M. Protein flexibility: differences especially observed in helices 1, 2, and 4.Conclusion. We present quantitative evidence that membrane composition subtly but significantly affects AQP1 dynamics. Our findings confirm the need for further progress in the study of the regulation of aquaporins by their lipid environment, avoiding generalized conclusions from a particular MDS system.