Award Abstract #2028803

RAPID: Structural Refinement and Intramolecular Binding in SARS-CoV-2 Spike Protein

See grant description on NSF site

Program Manager:

Daryl Hess

Active Dates:

Awarded Amount:



Wai-Yim Ching

Awardee Organization:

University of Missouri-Kansas City


Mathematical and Physical Sciences (MPS)


NONTECHNICAL SUMMARYThe current COVID-19 pandemic is a severe threat to human health leading to unprecedented social and economic disruption all over the world. All scientific organizations in different disciplines are fully mobilized to combat this terrible pandemic in various capacities. This award focuses on the fundamental understanding of the nature of this virus and how it attacks the human cell, leading to means to mitigate its detrimental effects. The research targets the structure and properties of a crucial COVID-19 protein using large-scale computational modeling. The objective is to obtain highly accurate and reliable structure data and investigate both inter-molecular and intra-molecular binding mechanisms at the atomic scale.The supported research is critically important in understanding the modification of the human cell under virus attack, providing insights for vaccine development and antivirus drug design at a much reduced cost by supplementing experimental data with computation. The fundamental understanding of the COVID-19 virus will have a profound socioeconomic impact domestically and internationally.TECHNICAL SUMMARYThis award supports the computational modeling and structure refinement of the SARS-CoV-2 spike protein. The research is challenging because of the structural complexity, the large number of atoms to be dealt with, the accuracy required for meaningful interpretation and the urgency associated with COVID-19 pandemic. This research includes the calculation of the electronic structure and interatomic bonding using first-principles density functional theory based on methods uniquely suited for this purpose. The spike (S) glycoprotein (S-protein) in SARS-COV-2 is the key element in understanding the anatomy of the virus, since it makes the first contact with the angiotensin converting enzyme (ACE2) in the human cell. The structure of the S-protein was determined by cryo-EM technique with a resolution of 3.5 Å. This resolution is not sufficiently fine for detailed calculations aimed at drug design. This research addresses that deficiency computationally. The S-protein consists of three chains (A, B, C), each consisting of four structural domains: receptor binding domain (RBD), N-terminal domain (NTD), and subdomains S1 and S2. This project will mostly focus on the RBD, which has 144 amino acids with a total of 2100 atoms. The structure of the entire Chain A in the spike protein has 959 amino acids and 14482 atoms. Refinement of the structures of these domains and investigation of the electronic structure and interatomic bonding, including hydrogen bonding, of the spike protein in both the pre- and post-fusion conformations provides the urgently needed information lacking in prior research. The structural data obtained here are to be deposited in an appropriate data bank and made available to the scientific community. This award supports the research using large-scale ab-initio computation, in conjunction with experimental verification, to identify the salient features in novel complex virus systems. Such a strategy is increasingly popular with the use of high accuracy cyro-EM measurements. The tightly coupled feedback between computational modeling, formal theory and experimental exploration is important for fundamental research in biomaterials and physical virology. The supported research has a wide range of broader impacts. First, novel insights generated from the research paves the way for applications in vaccine development and drug design. Second, the planned research aligns with educational goals by involving a postdoctoral fellow, graduate and undergraduate students, and external collaborators. This awarded project emphasizes the inclusion of women and minorities, where students work as a team in a boundary-free environment of modern science and engineering.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

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