Our research uses molecular dynamics (MD) simulations to explore how perturbations such as small molecules, mutations, and post-translational modifications affect the structure and dynamics of muscle proteins. With atomic resolution, these detailed simulations can visualize how changes at the single-atom scale allosterically propagate through complex molecular systems. In the cover image of the November 19 issue of Biophysical Journal, we compare and contrast MD-derived conformations of human cardiac β-myosin in the interacting heads motif state when either ADP×P_i×Mg²⁺ (the canonical ligand) or 2¢-deoxy-ADP×P_i×Mg²⁺ (a proposed therapeutic ligand) is bound in the active site.

ADP and 2¢-deoxy-ADP (dADP) differ by a single -OH group but have distinct dynamic behaviors when bound to myosin. The cover image includes 12 snapshots of ADP and dADP molecules extracted at different time points in our simulations, 2 snapshots of the myosin active site bound to either ADP (top) or dADP (bottom), and 6 snapshots of the myosin (blue) + essential light chain (green) + regulatory light chain (yellow) heterohexamer complex bound to either ADP (left) or dADP (right). The central snapshots show how myosin’s active site remodels in the presence of a dADP. Snapshots of the heterohexamer highlight differences in protein-protein complex interactions at the myosin-myosin interface and the myosin-light chain interfaces.

To create these images, we extracted atomic coordinates for different molecules from our MD simulations and rendered them with David Goodsell et al.’s Illustrate program (Structure 2019; 27:1716–1720.e1). Our major observation is that small-scale changes in ADP/dADP dynamics propagate through a complex molecule and remodel the protein active site and the architecture of the multiprotein complex. The results in our article provide powerful insights into the mechanisms by which a small molecule can activate a motor protein, making it a lead compound to treat certain forms of heart failure.  You can find more information about our work at https://sites.uw.edu/hammlab/ and https://ctmr.washington.edu.

— Matthew Carter Childers, Michael A. Geeves, and Michael Regnier