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

ABSTRACT

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.