When to Use Molecular Dynamics - Part 1 of 2

It can be tempting to think of molecular dynamics (MD) as an atomic-level microscope, able to describe arbitrary molecular interactions that are unobservable in the lab. But it’s important to remember that MD is a model that attempts to describe the molecular interactions in a very specific way. There is a particular functional form of the forces between any two atoms, and on top of this, there are many forcefields that parameterize these forces differently.

With this in mind, we need to always ask ourselves: “Can I trust the results of my simulation?” This is a difficult question to answer, but at least for the protein folding simulations that we do in the Pande group, we typically ask, “Are our simulations consistent with some experimental measurements of the same protein?” This can be a useful way to validate our simulations.

In addition to these concerns about the accuracy of the MD model, there are several more practical questions we should ask before beginning any simulation, specifically:

  • Is an MD simulation appropriate for the question that I'm asking?
  • Is an MD simulation possible given my computing resources and the system I am interested in?

I will address this first question here and tackle the second question in my next post.

“Is an MD simulation appropriate for the question that I’m asking?”

The power of a simulation is to provide insight that could not be gained in an easier way. Take for instance the field of protein folding. Here, there are numerous experiments that can measure low-dimensional projections of the very complex folding process. Drawing conclusions from these experiments, however, can be difficult since there may be many underlying mechanisms that are consistent with the data. This is where MD can be quite useful: it provides a physical model that can be used to interpret an experiment.  

It may be tempting to turn to simulation as another experimental technique for calculating measurable quantities. For instance, imagine that you’re working with a drug that binds to an enzyme and you’re interested in determining its binding constant, but don’t really care about the mechanism of binding. An experiment should be fully capable of measuring this binding constant, and a simulation would provide no further insight that you’re interested in! More importantly, remember that MD is ultimately just a model for the intrinsic dynamics, so it may turn out that the calculated binding constant is simply inconsistent with the experimental measurement.

The same can be said for other questions, where atomic-level detail is not necessary. For instance, consider a researcher that is interested in the relative diffusion constants between the dimeric and trimeric forms of a protein. A simpler model that does not attempt to describe the atomic-level interactions would likely be just as accurate as an MD simulation.  

Next, we need to consider the practicality of running an MD simulation.