Biology subjects

Algorta, J.

Publications and source records attributed to Algorta, J..

3 recordsLinked to original sources

bioRxiv2026

Mechanochemical Feedback Enables Efficient Navigation in Complex Chemical Gradients

Neutrophils move through narrow pores, convoluted channels, and tight spaces in tissue to find infection sites. Their ability to sense weak chemical gradients, undergo directed motion, and solve such path-finding problems rests on internal GTPase signaling circuits that control the front protrusion and rear retraction of the cell. Here we explore several variants of known core polarity circuits, with local and long-ranged negative feedback, including inhibitor downstream of Rac, Rac-Rho antagonism, and effects of membrane tension. The resulting reaction-diffusion (RD) equations for Rac and Rho are then used to simulate protrusion-retractions along the edge of a simulated motile cell. We visualize how cells navigate through narrow tracks with sharp corners and weak chemical gradients in 2D. Our metrics for cell performance include polarity initiation, wall-collision intensity, and track completion. In this way, we expose how Rac and Rho, together with their immediate down and upstream components can fine-tune neutrophil motility through complex environments. Author SummaryWhite blood cells, attracted to sites of infection, migrate through complex tissues to find their target. Such movement requires a balance between robust polarity in one direction versus flexibility in response to spatial cues such as obstacles and sharp turns. Here we use mathematical modeling to explore known intracellular circuits that regulate front protrusion and rear retraction in directed cell migration. We test several such circuits in simulations of cells moving along zigzag tracks with sharp turns. We demonstrate that a basic cell polarity circuit, on its own, has limited success, since cells tend to get trapped in sharp corners. Known modulators of this core, which add local negative feedback, mutual front-back antagonism, and long-range feedback from membrane tension, improve cell performance. A cell with the full front-back-membrane tension regulatory circuit avoids delays due to traps and obstacle collisions, and moves swiftly through a convoluted passage to its target site.

cell biology↗

bioRxiv2026

Is metabolism spatially optimized? Structural modeling of consecutive enzyme pairs reveals no evidence for spatial optimization of catalytic site proximity.

Metabolic pathways are often hypothesized to benefit from the spatial organization of enzymes, facilitating substrate transfer through mechanisms such as metabolic channeling or metabolon formation. However, it remains unclear whether the spatial proximity of catalytic sites represents a general organizational principle of metabolism or is restricted to specific pathways. Here, we investigate whether consecutive enzymes in metabolic pathways, when physically interacting, exhibit structurally optimized arrangements that minimize distances between their catalytic sites, thereby increasing metabolite transfer efficiency from one enzyme to the next. We first evaluated the ability of current protein-protein interaction prediction methods, including AlphaFold2, AlphaFold3, ESMFold, and HDOCK, to model weak and transient interactions using a benchmark dataset of 112 low-affinity protein dimers from PDBbind. AlphaFold-based approaches performed best in recovering correct interaction geometries, while ESMFold showed limited performance. We further assessed several confidence metrics and identified ipTM, ipSAE, and VoroIF-GNN as the most informative predictors of correct interaction conformations. In addition to simple Euclidean distance metrics, we developed a computational procedure to estimate shortest accessible space paths between catalytic sites in predicted enzyme-enzyme complexes. Applying this framework to 107 consecutive enzyme pairs in E.coli revealed an increased tendency for consecutive enzymes to interact, but no systematic evidence that interacting enzymes position their catalytic sites in spatially optimized configurations. In the predicted complex conformations, catalytic sites tend not to be positioned closer than expected at random. The developed computational workflow provides a general framework for analyzing structural aspects of metabolic organization.

bioinformatics↗

bioRxiv2025

Investigating Local Negative Feedback of Rac Activity by Mathematical Models and Cell Motility Simulations

For polarization and directed migration, cells use a combination of local positive feedback and long-range inhibition. We have previously used mathematical models to show the ability of this core circuit to regulate directed cell movement. However, this wave pinning model lacks important additional feedback circuits, including the recently demonstrated local negative feedback from Town and Weiner. Here we extend our models to investigate the consequences of this additional link on cell physiology. We model responses of neutrophil-like HL-60 cells to spatially-controlled optogenetic stimulation of PI3K, leading (via PIP3) to Rac activity. We sequentially build up and investigate partial differential equation (PDE) models of the key Rac, Rac-Inhibitor, and PIP3-Rac-Inhibitor circuits. We fit model parameters to temporal and spatial (cell trajectory) data. Cell shapes, motility, and responses to stimuli are modeled in 2D cell-based simulations, with PDEs for Rac and the other regulatory components solved along the cell edge. We demonstrate that the ability of modeled cells to respond to temporal as well as spatial features of guidance cues depends on the addition of the local negative feedback circuit. Furthermore, the local Rac inhibitor improves the ability of modeled cells to respond to noisy or dynamic extracellular gradients. Our work demonstrates how local negative feedback enhances dynamic polarity and gradient sensing in migratory cells.

cell biology↗