Team 4: simulating molecular dynamics of potential drug target regions
The ras family of G-proteins is one of the most important and universally mutated proteins in cancer. Due to its small size and lack of obvious binding pockets, it is currently undruggable by any direct means. However, the static high-resolution structural information may obscure transient conformations containing pockets that may be directly or allosterically targeted by small molecules. Here, we provide a 20 microsecond-long all-atom molecular dynamics simulation trajectory of H-ras at thermal equilibrium under physiological conditions. The goal is to identify the shape and location of transient pockets that may be stabilized through binding of targeted molecules, and to correlate the emergence of such pockets with structural changes in the protein active site. Establishing the lack of druggable pockets within the transient ensemble would also be a valuable result. The findings may stimulate future docking simulations with designed ligands, as well as experimental tests of ligand binding and control.