Elucidation of Cryptic and Allosteric Pockets within the SARS-CoV‑2 Main Protease

The
SARS-CoV-2 pandemic has rapidly spread across the globe, posing
an urgent health concern. Many quests to computationally identify
treatments against the virus rely on in silico small
molecule docking to experimentally determined structures of viral
proteins. One limit to these approaches is that protein dynamics are
often unaccounted for, leading to overlooking transient, druggable
conformational states. Using Gaussian accelerated molecular dynamics
to enhance sampling of conformational space, we identified cryptic
pockets within the SARS-CoV-2 main protease, including some within
regions far from the active site. These simulations sampled comparable
dynamics and pocket volumes to conventional brute force simulations
carried out on two orders of magnitude greater timescales.