How a SARS-CoV-2 variant sacrifices tight binding for antibody escape – sciencedaily

The highly infectious variant of SARS-CoV-2 that has recently emerged in South Africa, known as B.1.351, has scientists wondering how existing COVID-19 vaccines and therapies can be improved to ensure a strong protection. Now researchers report in ACS Journal of Medicinal Chemistry used computer modeling to reveal that one of three mutations that make the B.1.351 variant different from the original SARS-CoV-2 reduces the virus’s binding to human cells – but potentially allows it to escape certain antibodies.

Since the original SARS-CoV-2 was first detected in late 2019, several new variants have appeared, including those from the UK, South Africa and Brazil. Because the newer variants appear to be more highly transmissible and therefore spread rapidly, many people worry that they could compromise current vaccines, antibody therapies, or natural immunity. The B.1.351 variant carries two mutations (N501Y and E484K) that may enhance the binding between the receptor binding domain (RBD) of the coronavirus spike protein and the human ACE2 receptor. However, the third mutation (K417N; a mutation from lysine to asparagine at position 417) is puzzling because it eradicates a favorable interaction between RBD and ACE2. Therefore, Binquan Luan and Tien Huynh of IBM Research wanted to study the potential benefits of the K417N mutation that could have caused the coronavirus to evolve along this path.

The researchers used molecular dynamics simulations to analyze the consequences of the K417N mutation in the B.1.351 variant. First, they modeled the binding between the original SARS-CoV-2 RBD and ACE2, and between RBD and CB6, which is a SARS-CoV-2 neutralizing antibody isolated from a recovered COVID-19 patient. They found that the original amino acid, a lysine, at position 417 in RBD, interacted more strongly with CB6 than with ACE2, consistent with the therapeutic efficacy of the antibody in animal models. Next, the team modeled the binding with the K417N variant, which turns this lysine into asparagine. Although this mutation reduced the binding strength between RBD and ACE2, it decreased the binding of RBD to CB6 and several other human antibodies to a much greater extent. Thus, the B.1.351 variant appears to have sacrificed the tight binding to ACE2 at this site for the ability to evade the immune system. This information could prove useful for scientists as they work to improve the protection of current vaccines and therapies, the researchers say.

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