PROJECT SUMMARY We propose to develop a novel computational platform, called TRACTOR, to couple theoretical models of cell motility and cell-matrix interaction with a sophisticated model of matrix mechanics and reorganization. TRACTOR will address a significant technology gap by providing a link between cell mechanics and matrix mechanics, both of which have been studied extensively but whose synergistic interplay remains largely unexplored. For this proof-of-concept study, the matrix will be represented as a network of type I collagen fibers, as in commonly-used collagen gel assays, modeled as a semiflexible string of beads connected by harmonic bonds. The action of the cell will be modeled by introducing a separate set of isolated beads - called "tractors" - that (1) extend from the cell, (2) attach to nearby collagen fibers, (3) retract back to the cell, dragging the collagen with them, and (4) release the collagen. A critical element of the process is that after the third step, collagen beads that have been brought into close contact by the action of the tractors will form new bonds, creating the plasticity reported by multiple researchers in collagen mechanics. The new bond formation introduces irreversibility to the process, so the matrix released in step (4) does not return to its pre-step-(1) configuration. As the cycle repeats, the cell will be able to induce large deformations of the matrix even though each individual tractor generates relatively small amounts of motion. A key feature of the TRACTOR platform, to be developed during this initial study but implemented only in its simplest form for exploratory purposes, will be its flexibility to accommodate different models of cell mechanics and matrix mechanics and composition. TRACTOR will also be computationally innovative, leveraging the open-source LAMMPS software's energy minimization functionality; this functionality, normally used as a prelude to molecular dynamics calculations, will be repurposed to provide an efficient, flexible base for TRACTOR and for long-term distribution of the TRACTOR code to other users. Key proof-of-concept milestones proposed herein are based on well-established experimental observations: (1) a working TRACTOR model of a cell compacting the matrix around it, (2) a working TRACTOR model of a cell polarizing and exerting anisotropic traction in an anisotropic collagen gel, and (3) a working TRACTOR model of multiple cells interacting mechanically within a collagen gel. Achievement of these milestones will demonstrate the potential of the TRACTOR framework and justify further pursuit of it as a modeling tool for theoretical studies of cell-matrix interaction.

PROJECT NARRATIVE Many important biological processes - in both health and disease - involve cells sensing, responding to, and changing the non-cellular tissue that surrounds them. We will create a new modeling software platform that allows more in-depth study of (1) how the cell changes the material around it, and (2) how those changes lead to subsequent changes in cell behavior. In this study, we are testing our envisioned computational platform with a series of test problems based on published experimental observations.