Abstract
The SARS-CoV-2 spike has been regarded as the main target of antibody design against COVID-19. Two single-site mutations, R190K and N121Q, were deemed to weaken the binding affinity of biliverdin although the underlying molecular mechanism is still unknown. Meanwhile, the effect of the two mutations on the conformational changes of “lip” and “gate” loops was also elusive. Thus, molecular dynamics simulation and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation were conducted on the wild-type and two other SARS-CoV-2 spike mutants. Our simulations indicated that the R190K mutation causes Lys190 to form six hydrogen bonds, guided by Asn99 and Ile101, which brings Lys190 closer to Arg102 and Asn121, thereby weakening the interaction energy between biliverdin and Ile101 as well as Lys190. For the N121Q mutation, Gln121 still maintained a hydrogen bond with biliverdin; nevertheless, the overall binding mode deviated significantly under the reversal of the side chain of Phe175. Moreover, the two mutants would stabilize the lip loop, which would restrain the meaningful upward movement of the lip. In addition, N121Q significantly promoted the gate loop deviating to the biliverdin binding site and compressed the site. This work would be useful in understanding the dynamics binding biliverdin to the SARS-CoV-2 spike.
Highlights
Since the advent of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), significant threats have been posed to the human population worldwide (Wang et al, 2020)
To figure out the impact of single-site mutations on the interactions of SARS-CoV-2 spike binding with biliverdin, three systems were constructed, including SpikeWT/Biliverdin, SpikeN121Q/Biliverdin, and SpikeR190K/Biliverdin
The SpikeWT/Biliverdin system was acquired from its corresponding X-ray crystal structure (PDB ID: 7b62), while the other two single-site mutations were constructed based on the system of SpikeWT/Biliverdin in Sybyl-X2.1
Summary
Since the advent of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), significant threats have been posed to the human population worldwide (Wang et al, 2020). The spike protein trimers, a protruded structure that exists on the SARS-CoV-2 virions, are able to bind to a surface receptor on the cell and accommodate fusion of the viral and cellular membranes when they are glycosylated. For these reasons, with perfect conformational flexibility (Ke et al, 2020), the SARS-CoV-2 spike is a crucial viral antigen and the target in designing antibodies, which lead to its support for the current critical SARS-CoV-2 vaccine development efforts (Tregoning et al, 2020). The relevance between mutations in the SARS-CoV-2 spike NTD and viral escape from antibody immunity
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