ABSTRACT
The never-ending emergence of SARS-CoV-2 variations of concern (VOCs) has challenged the whole world for pandemic control. In order to develop effective drugs and vaccines, one needs to efficiently simulate SARS- CoV-2 spike receptor binding domain (RBD) mutations and identify high-risk variants. We pretrain a large pro- tein language model on approximately 408 million pro- tein sequences and construct a high-throughput screen- ing for the prediction of binding affinity and antibody escape. As the first work on SARS-CoV-2 RBD mu- tation simulation, we successfully identify mutations in the RBD regions of 5 VOCs and can screen millions of potential variants in seconds. Our workflow scales to 4096 NPUs with 96.5% scalability and 493.9X speedup in mixed precision computing, while achieving a peak performance of 366.8 PFLOPS (reaching 34.9% theo- retical peak) on Pengcheng Cloudbrain-II. Our method paves the way for simulating coronavirus evolution in or- der to prepare for a future pandemic that will inevitably take place.
ABSTRACT
The burgeoning epidemic caused by novel coronavirus 2019 (2019-nCoV) is currently a global concern. Angiotensin-converting enzyme-2 (ACE2) is a receptor of 2019-nCoV spike 1 protein (S1) and mediates viral entry into host cells. Despite the abundance of ACE2 in small intestine, few digestive symptoms are observed in patients infected by 2019-nCoV. Herein, we investigated the interactions between ACE2 and human defensins (HDs) specifically secreted by intestinal Paneth cells. The lectin-like HD5, rather than HD6, bound ACE2 with a high affinity of 39.3 nM and weakened the subsequent recruitment of 2019-nCoV S1. The cloak of HD5 on the ligand-binding domain of ACE2 was confirmed by molecular dynamic simulation. A remarkable dose-dependent preventive effect of HD5 on 2019-nCoV S1 binding to intestinal epithelial cells was further evidenced by in vitro experiments. Our findings unmasked the innate defense function of lectin-like intestinal defensin against 2019-nCoV, which may provide new insights into the prevention and treatment of 2019-nCoV infection.