To fill this gap, the team coordinated by Gerhard Hummer developed dynamic molecular simulations so that it was possible to have the complete structure of the spike protein and its movements in a real environment.
These simulations ended up showing that the glycans in the spike protein act as a dynamic shield that helps the virus escape the human immune system. In a statement, the team compares glycans to windshields in a car: by balancing up and down, they cover all the protein, even if their coverage is minimal at any time.
By combining dynamic simulations of the protein with bioinformatics analyzes, areas on its surface were identified that are less protected by the glycans shield. Some of these sites have already been detected, but others are new. Now, the vulnerability of many of these new locations will have to be confirmed by other teams with laboratory experiments.
In a comment on this work, Diana Lousa, a scientist at the Institute of Chemical and Biological Technology (ITQB) of the Universidade Nova de Lisboa, starts by highlighting to the PUBLIC that it is known that the spike protein is essential in the process of entering the virus in our cells and the main target of our immune system. Therefore, they are the focus of numerous vaccines. “It is necessary to know the structure very well and, at this moment, there are already several dozen experimental studies that give us a detailed picture of this structure”, reports the researcher who did not participate in the study now published.
However, he stresses that some pieces of this puzzle: “There are parts of the protein that are not visible experimentally and we are not able with these methods to understand how it moves to ‘open the door’ of our cells and to escape the immune system”, he explains. “In this study, they used molecular simulation methods, which are a kind of ‘digital microscope’.”
From a photograph to a film
The researcher describes that in this investigation, using very realistic computational models, it was possible to reconstitute the missing pieces of the protein, as well as observe its movements and see it in action. “We stopped having just a static photo and started to have a dynamic film.”
And what could be the contribution? “This allowed us to better understand which areas are exposed to antibodies and to predict which regions we can use to develop future vaccines”, notes Diana Lousa. This new work thus allows to better understand one of the main targets of SARS-CoV-2 and provides important clues that can be used in the development of new vaccines and drugs, which can be “more focused on specific regions of this protein and that can be effective against several variants ”, perspective.
To the PUBLIC, Mateusz Sikora (researcher at the Max Planck Institute of Biophysics and first author of the article) detailed that the “most interesting” is that new sites now identified are located in different parts of the spike protein and, thus, many antibodies (the our organism’s defenses) can connect to them simultaneously. “This means that if we are able to trigger an immune response against some of them, then the virus will have little ability to mutate and escape vaccines,” he says.
Although the model was made before the variants of concern were known, it was concluded that it remains valid for them. “The sites we detected will not be much more protected in the variants than in the original virus”, says the researcher. If a variant with a very different protection by glycans appears, then the simulations will have to be redone and the now detected sites evaluated again.
“We are in a phase of the pandemic that is driven by the emergence of new variants of SARS-CoV-2, with mutations concentrated mainly on the spike protein [como é o caso da inicialmente detectada no Reino Unido, África do Sul e Manaus]”, He comments. “Our approach can help with the design of vaccines and therapeutic antibodies.” Mateusz Sikora says the results had already been made available online a few months ago and that this has aroused the interest of different laboratories. The team also hopes that the same method will be used to identify vulnerabilities in other viral proteins.
In the ITQB Protein Modeling laboratory, where Diana Lousa works, molecular simulation methods are also being used to understand, for example, how the spike protein interacts with the receptor on our cells or what the impact of new variants on this interaction. Computational models are also used to project proteins that do not exist in nature so that it can block the virus from entering cells.
There are already some interesting and promising preliminary results, but the researcher says that more news and “more closed things” will appear in the coming months. For now, he just underlines: “These computational methods play an increasingly important role in modern biology and, as we saw in this study, are complementary to experimental methods”.
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