Mutations of Omicron Variant at the Interface of the Receptor Domain Motif and Human Angiotensin-Converting Enzyme-2

Abstract

The most recent Omicron variant of SARS-CoV-2 has caused global concern and anxiety. The only thing certain about this strain, with a large number of mutations in the spike protein, is that it spreads quickly, seems to evade immune defense, and mitigates the benefits of existing vaccines. Based on the ultra-large-scale ab initio computational modeling of the receptor binding motif (RBM) and the human angiotensin-converting enzyme-2 (ACE2) interface, we provide the details of the effect of Omicron mutations at the fundamental atomic scale level. In-depth analysis anchored in the novel concept of amino acid-amino acid bond pair units (AABPU) indicates that mutations in the Omicron variant are connected with (i) significant changes in the shape and structure of AABPU components, together with (ii) significant increase in the positive partial charge, which facilitates the interaction with ACE2. We have identified changes in bonding due to mutations in the RBM. The calculated bond order, based on AABPU, reveals that the Omicron mutations increase the binding strength of RBM to ACE2. Our findings correlate with and are instrumental to explain the current observations and can contribute to the prediction of next potential new variant of concern.

Keywords: AABP unit; Omicron variant; SARS-CoV-2; complexity in shape and volume; partial charge; spike protein; virial transmission.

Figure 1

The RBM-ACE2 interface model. (a) Ribbon structure showing the interface between the RBM and segment of ACE2. Ten mutated AAs of the RBM in OV are marked. (b) The ball and stick structure of the same model in (a): Grey: C; red: O, blue: N; and white: H. In the WT interface model, there are 1102 atoms in RBM, 1822 atoms in ACE2 segment, and 6 Na⁺ ions, with a total of 2930 atoms. In OV interface model, there are 1141 atoms in RBM, 1822 atoms in ACE2 segment, and 1 Na⁺ ions with a total of 2964 atoms.

Figure 2

Details of the shape change of AABPU of the ten mutation sites in RBM: (a) N440, (b) G446, (c) S477, (d) T478, (e) E484, (f) Q493, (g) G496, (h) Q498, (i) N501, and (j) Y505 for the WT. (a′) K440, (b′) S446, (c′) N477, (d′) K478, (e′) A484, (f′) R493, (g′) S496, (h′) R498, (i′) Y501, and (j′) H505 for the OV. The surface of mutated sites is shown in magenta, and surfaces of NN and NL are shown in yellow and green, respectively. All NN and NL AAs are marked near to their surface in brown and black, respectively. NL AAs from ACE2 are marked in red.

Figure 3

Interaction change due to mutation at site 498 for both WT (left) and OV (right). The surface of site 498 is marked in magenta color. The surfaces of its NN AAs and NL AAs are shown in yellow and green, respectively. Visible NN and NL AAs are marked near their surface in brown and black, respectively. NL AAs from ACE2 are marked in red. We can see considerable changes in NL AAs and their shapes due to mutation.

Figure 4

Comparison of RBM–ACE2 interaction in the interface model for WT and OV. (a) AABP map focusing on changes in bonding at the interface of mutated sites for WT (black) and OV (red). (b) Interactions at the RBM-ACE2 interface for OV. Interface-interacting AAs in RBM are shown in blue and red circles, denoting mutated and unmutated AAs, respectively. Similarly, interacting AAs of ACE2 are shown in purple. Different colored lines are used just for clarity. (c) AABP map focusing on changes in bonding of interface of unmutated sites for WT (black) and OV (blue).

Figure 5

Partial charge (PC) for 10 sites before and after mutation: (a) PC per AABPU (PC*) for 10 sites (b) PC for each AA (PC^AA). One out of ten mutated AABPU (Y505H) flips from positive PC* to negative PC* in relatively small amount. The PC* for mutation Q498R AABPU more than doubled. Two out of ten AAs (G496S and Y505H) PC^AA value increase in the negative direction. The blue and red (*) signs denote AAs in WT and OV, respectively, that interact with ACE2.

Figure 6

PC* vs. volume for 10 sites before and after mutation.