Modeling of AQP4 diffusion in the plasma membrane of extending lamellipodia predicts size- and composition-dependent sieving of orthogonal arrays. (A) Dependence of AQP4 diffusion coefficient, D, on array size (number of tetramers/array), deduced from single-particle tracking data (Crane et al., 2009) and dSTORM imaging (Rossi et al., 2012b). (B) Schematic showing two-dimensional diffusion of AQP4 particles into an extending lamellipodium of length 5 µm, with 50 µm × 50 µm cell body. (C) Computations showing the distribution of AQP4 particles just after a lamellipodia extension, for indicated M1/M23 ratios of 1:0, 1:1, 1:3, and 0:1. Filled circles encode particle sizes, and color encodes percentage of M1–AQP4 in each particle. (D) Distribution of AQP4 isoforms, size, and diffusion computed just after a lamellipodial extension for M1/M23 of 1:1 and 1:3. Computations show relative M1–AQP4 enrichment in lamellipodia (top), with reduced AQP4 array size (middle), and increased AQP4 diffusion (bottom).