A Primer on Molecular Dynamics

Summary

IntroductionHow does MD work in practice?System DefinitionForce Fields The basic definitionThe detailsEnergy minimization + equilibration Production simulationInteresting miscellaneous thingsBypassing small timescalesQuantum effects Free energy calculationsCase studies Discovery of lirafugratinib (RLY-4008), a highly selective irreversible small-molecule inhibitor of FGFR2Characterizing Receptor Flexibility to Predict Mutations That Lead to Human Adaptation of Influenza HemagglutininConclusionI’ve recently become very interested in molecular dynamics, or MD. Why would you want to do MD at all? MD allow you to watch molecules dance in full atomic detail. While experimental techniques give you static molecular mugshots, MD lets you observe the dynamic behavior of molecules over time. And understanding molecular motion is key for everything in biology, everything in biology is vibrating molecules underneath the surface! Beyond just watching, you can use MD to predict molecular behavior. Want to know how tightly a drug will bind its target? Run an MD simulation and calculate the binding free energy. Trying to design a new enzyme? Simulate different designs to see which folds and functions best. Obviously, there are limitations — as we’ll get into — but the possibilities the field presents are fascinating. Unfortunately, MD also happens to be incredibly hard to learn on your own. Unlike my other posts, where I can go from nearly zero knowledge to blog-post-capable in a week, MD has taken me the better part of a month and I’m still unsure of a lot of things. I’m much more used to the general fuzziness of ML; extremely overparameterized statistical models that can actively learn means that their exact theoretical underpinnings are, at best, interesting, but rarely useful outside of a few cases. So, hand-waving is practically fine! This isn’t the case in MD, all of it feels important to know and understand. You’re dealing with physics after all, and even if you hand-wave aw...