期刊
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
卷 90, 期 5, 页码 1044-1053出版社
WILEY
DOI: 10.1002/prot.26208
关键词
coronavirus; molecular dynamics simulation; protein conformation; protein dynamics; protein modeling; SARS-CoV-2; spike glycoprotein
资金
- National Institutes of Health [GM136431]
- Rutgers University Center for COVID-19 Response and Pandemic Preparedness (CCRP2) research grants
Through molecular dynamics simulations, researchers have found that the receptor-binding domain of the SARS-CoV-2 virus exhibits local dynamic flexibility in the unbound state, with mutations in the Loop 3 region having no effect on this flexibility. They have identified novel unbound substates of the RBD that are lower energy than the ACE2-bound conformation, potentially serving as new targets for therapeutic design.
Since the identification of the SARS-CoV-2 virus as the causative agent of the current COVID-19 pandemic, considerable effort has been spent characterizing the interaction between the Spike protein receptor-binding domain (RBD) and the human angiotensin converting enzyme 2 (ACE2) receptor. This has provided a detailed picture of the end point structure of the RBD-ACE2 binding event, but what remains to be elucidated is the conformation and dynamics of the RBD prior to its interaction with ACE2. In this work, we utilize molecular dynamics simulations to probe the flexibility and conformational ensemble of the unbound state of the receptor-binding domain from SARS-CoV-2 and SARS-CoV. We have found that the unbound RBD has a localized region of dynamic flexibility in Loop 3 and that mutations identified during the COVID-19 pandemic in Loop 3 do not affect this flexibility. We use a loop-modeling protocol to generate and simulate novel conformations of the CoV2-RBD Loop 3 region that sample conformational space beyond the ACE2 bound crystal structure. This has allowed for the identification of interesting substates of the unbound RBD that are lower energy than the ACE2-bound conformation, and that block key residues along the ACE2 binding interface. These novel unbound substates may represent new targets for therapeutic design.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据