Protein Mechanica: Structural Modeling for the Experimentalist

Scientists sometimes find themselves up to their elbows in Styrofoam balls, pipe cleaners, and metal rods as they try to build models of the molecules they are studying. Now, they can exchange all that for the ease and precision of a computer. With the alpha release of the modeling software Protein Mechanica, researchers have a new option for constructing plausible models of molecules based on experimental data, such as x-ray crystallography and cryo-electron microscopy (cryo-EM), and then simulating and visualizing their conformations.

The model-building component is a unique aspect of the software, says David Parker, a recent Simbios student who developed the software as part of his PhD thesis. The software has been used to reproduce experimental observations of a myosin V, a protein that moves cellular cargo along actin filaments, but Parker points out that it is new and they are still validating it. “There’s no software that does this kind of thing, so we are still trying to understand how to apply different coarse-graining modeling strategies. The more systems we work on, the better we understand how to parameterize the models.”

Designed for and in collaboration with experimentalists, Protein Mechanica uses their language to build the model. “Protein Mechanica will allow anyone to sit down and build these models,” Parker says. “You use protein chain and residue identifiers and atom names, so in a script of only two lines you can build a complete mechanical model of a large molecular system.”

With Protein Mechanica, researchers will be able to construct models using information from a variety of sources: crystallography, cryo-EM, secondary structure descriptions, as well as user-defined solid shapes, such as spheres and cylinders. This flexibility is useful since crystal structures typically contain only molecular fragments, requiring that different crystal structures be integrated or that missing pieces be represented by other means in order to produce a complete model.

By working closely with experimentalist Zev Bryant, PhD, an assistant professor of bioengineering at Stanford University, Parker identified what is really important, and it did not require full-blown dynamics. Experimentalists just need a tool that can quickly show them how different parts of a molecule interact mechanically. They do not need or want to spend weeks simulating the diffusion process of the molecule.

“Just the geometric constraints of the model alone can provide insights,” says Parker. “For instance, one part of a molecule might be unable to move a particular way if there’s not enough room.” So Protein Mechanica evolved into a tool for building structures and modeling their plausible conformations. It holds promise for changing the way some experimentalists work. “The software is helping us fill a major deficiency in single molecule [experimental] work,” says Bryant. Single molecule measurements provide clues as to how a molecule moves, but they cannot reveal the entire picture of what is happening, particularly at the atomistic level. Modeling can help fill in the gap, as well as aid in the design of new molecules. Protein Mechanica is particularly useful because it enables comparisons between its predictions and experimental data at various levels of spatial resolution.

Bryant says his students can now quickly take any myosin they’re working on, build hypothetical conformations, and compare measurements from the model with measurements taken from single molecule assays. “Protein Mechanica is very well-suited for that task and I think very expandable,” he says.

DETAILS

Protein Mechanica is freely available for download from https://simtk.org/home/protmech.