Center for Quantiative Biological Simulation Microphysiology Gateway

MCell Overview

Typical events that occur during an MCell simulation include the release of ligand molecules from a structure (e.g., a vesicle), de novo creation or destruction of ligand molecules (e.g., synthesis, hydrolysis, or redox reactions), ligand diffusion within spaces defined by arbitrary surfaces (e.g., pre- and postsynaptic membranes, or a cell membrane with attached patch clamp micropipette), and chemical reactions undergone by ligand and "effector" (e.g., receptor or enzyme) molecules. Ligands, effectors, reaction mechanisms, 3-D surfaces, and other simulation components are specified using a simple programming language, or Model Description Language (MDL), that was designed with biologically-oriented users in mind. When a simulation is run, one or more MDL input files are interpreted (parsed) to create the simulation objects, and then execution begins for a specified number of iterations. Each iteration corresponds to one Monte Carlo time-step. A wide variety of numerical and imaging results can be output from the run, and, in addition, simulations can be stopped and subsequently restarted from user-specified "checkpoints." Each time that a simulation restarts, updated information can be read from the input MDL file(s). Checkpointing is thus a powerful and general way to change run-time parameters such as the time-step, reaction rate constants, and surface positions, and can also be used to split long simulations into segments that are run sequentially.

MCell's Monte Carlo algorithms simulate ligand diffusion using 3D random walk movements for individual molecules. The positions of surfaces and effector sites are mapped in space, and "encounters" with diffusing ligand molecules are detected at points of intersection with the ligand's motion. The final outcome of each encounter is decided by comparing the value of a random number to the probability of each possible outcome. Different possible outcomes depend on the properties of the surface. For example, at the point of intersection, the surface may be reflective, transparent, absorptive, or occupied by an effector site with an associated chemical reaction mechanism. Random numbers are also used to decide between all other possible reaction mechanism transitions that might occur during each time-step. For example, bound ligand molecules may unbind, and effector sites may change from one defined state to another, simulating a protein conformational change.

The numerical accuracy of MCell's algorithms has been rigorously tested, and because of unique optimizations the time required for simulations does not depend on the complexity of included surfaces. In other words, simulation of a large-scale tissue reconstruction (e.g. hundreds of thousands of polygons) requires about the same amount of time as simulation of a highly simplified structure. The effective speed-up introduced by our code optimizations thus amounts to many orders of magnitude, and can literally save months of computer time.

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