Efforts to contain the spread of SARS-CoV-2 may benefit from a new analytical tool developed by a team led by biologists at 电子游戏软件, who report their computer simulation of molecular interactions can predict mutations of the virus and help develop insights into future variants of concern before they emerge.
“We computationally predict what mutations allow better binding to host receptors and better evasion of antibodies,” said 电子游戏软件 Assistant Professor of 生物学 Babak摩, 该项目的首席电子游戏正规平台员. “Such mutations can potentially lead to a future variant of concern. Having this knowledge from our model would help with readiness for detecting and preventing, 还有治疗, 正在出现的和未来的变体.”
Quantum mechanical modeling allowed the team to develop an initial set of predictions about the role of mutations on infectivity and immune response evasion of Omicron and other SARS-CoV-2 variants with human host cells, 摩曼说. 冠状病毒的刺突蛋白, 或SARS-CoV-2, 与ACE2结合, 寄主细胞上的受体, which allows the virus to enter the cells and infect it. Binding is the first step for infection, and several mutations in previous variants of concern have been shown to be important for increasing the spike's binding to human ACE2.
“We simulated the electronic structure of the two interacting molecules and assessed how amino acids of the spike and ACE2 interacted with their counterparts. We also evaluated how mutating individual amino acids could change the interaction.”
电子游戏正规平台ers have deployed a number of computational methods to examine the spike-ACE2 interaction. 的 从头开始 量子力学模型方法, which is focused on the electron structure, is considered to be highly accurate and able to examine both short-range and long-range interactions among amino acid residues, 摩曼说.
的 Omicron variant of the coronavirus is suspected to be the most infectious yet by binding to human receptors better than the Delta variant and the team’s findings show it may have the potential to continue to evolve even stronger binding to increase transmission and infectivity, according to a pre-print of a new study completed by the team.
Assistant Professor of 生物学 Babak摩
冠状病毒的刺突蛋白, 或SARS-CoV-2, binds to 寄主细胞上的受体, 叫ACE2, which allows the virus to enter the cells and infect it. Binding is the first step for infection, and several mutations in previous variants of concern have been shown to be important for increasing the spike's binding to human ACE2.
“We use a fully quantum mechanical model to theoretically assess how different mutations in the spike can contribute to its increased, 或减少, 与人ACE2的结合强度,莫米尼说。. “的 modeling shows that Omicron binds to receptor proteins stronger than the currently dominant Delta variant.”
除了Momeni, 电子游戏软件 Professor of 生物学 Welkin Johnson and post-doctoral researcher Marco Zaccaria, Luigi Genovese of French CEA - University of Grenoble Alpes, and Professor Michael Farzan of the Scripps 电子游戏正规平台 Institute, 对报告有贡献 "Investigating the mutational landscape of the SARS-CoV-2 Omicron variant via 从头开始 量子力学建模” which is available at the pre-print host site bioRxiv.
“We find that Omicron has not reached its full potential to bind human host cells,莫米尼说。. “We identify mutations that can strengthen the virus affinity for the human cell, which could increase infectivity and evasion of antibodies.” He cautioned that increased infectivity is only one important aspect in variants of concern; it is also important to monitor the severity of symptoms and the ability of the variant to evade antibodies and vaccines.
While the study found that Omicron’s spike proteins bind better than the Delta variant to the human ACE2 receptor, not all mutations in the spike protein’s targeting system—known as a receptor binding domain—are beneficial for binding, which suggests factors other than binding may also be involved in determining how the variant evolves.
One possible explanation is that the variant has acquired mutations to evade host antibodies, 摩曼说. Such mutations can be detrimental to its binding to the host receptor and were followed by additional compensatory mutations to recover, 甚至提高, 它的受体结合.
摩曼说 the team was surprised to see a range of mutations—some beneficial, 一些中立的, 还有一些对hACE2结合有害. He said the team’s next steps are to experimentally validate the predictions of the model.
的 team’s findings on Omicron build upon a prior analysis of the Wuhan and Delta variants by the team. 在那里, modeling found that E484 was actually a “weak link” in the original Wuhan strain, but it has evolved through mutation to better bind to human host cells and to evade some antibodies, 摩曼说. 另外, the team found that the Wuhan strain binding to ACE2 in bats was more optimized than the human counterpart. 的 team predicted further E484K mutation added to the Delta variant would produce a future variant of concern.
Ed Hayward | University Communications | December 2021