Proteins are microscopic machines involved in nearly all aspects of life. For them to work correctly, most need to fold into precise three dimensional structures that enable their atoms to catalyze chemical reactions, bind to other molecules, and produce mechanical forces. Traditional efforts to understand how these processes work have focused on the area of the protein immediately around where it interacts with other molecules (sometimes called the “first shell” of the active site or binding site). This region typically represents a small fraction of the protein, with the rest of the structure usually assumed to only serve as a static scaffold for the functional part. However, many recent studies have started to challenge this assumption and show that regions far removed from the functional site play a much more dynamic role.

The Smith Lab aims to determine the atomic-level mechanisms of how changes in the so-called “second shell” and beyond propagate through the protein and ultimately affect function. This can enable protein activity to be regulated by distant events through a process called allostery. Furthermore, deleterious mutations far removed from the active site make the protein malfunction and cause disease. In other cases, protein engineering has discovered unusually located mutations that enhance activity, making synthetic and therapeutic applications possible. The common mechanistic question about these examples is the following: how do atomic rearrangements propagate from one part of the structure to another? Even more intriguingly, how can a signal propagate without distinct structural changes? There are an increasing number of cases where this communication happens not through a change in the structure of the protein, but in the amount of motion.

Our efforts to answer these questions take a distinctly multidisciplinary approach. We use computational simulation and modeling, which provides an extraordinary amount of detail. We also make use of high-resolution biophysical techniques like nuclear magnetic resonance (NMR) to accurately determine both structure and dynamics at the atomic level. To enhance our investigations, we develop new computational techniques to better harness experimental data for simulation and modeling. The overarching goal of our studies is to better understand how protein activity is remotely controlled by nature and ultimately enable rational manipulation for therapeutic or synthetic applications.