Structural bioinformatics analysis of SARS-CoV-2 variants reveals higher hACE2 receptor binding affinity for Omicron B.1.1.529 spike RBD compared to wild type reference

Abstract

To date, more than 263 million people have been infected with SARS-CoV-2 during the COVID-19 pandemic. In many countries, the global spread occurred in multiple pandemic waves characterized by the emergence of new SARS-CoV-2 variants. Here we report a sequence and structural-bioinformatics analysis to estimate the effects of amino acid substitutions on the affinity of the SARS-CoV-2 spike receptor binding domain (RBD) to the human receptor hACE2. This is done through qualitative electrostatics and hydrophobicity analysis as well as molecular dynamics simulations used to develop a high-precision empirical scoring function (ESF) closely related to the linear interaction energy method and calibrated on a large set of experimental binding energies. For the latest variant of concern (VOC), B.1.1.529 Omicron, our Halo difference point cloud studies reveal the largest impact on the RBD binding interface compared to all other VOC. Moreover, according to our ESF model, Omicron achieves a much higher ACE2 binding affinity than the wild type and, in particular, the highest among all VOCs except Alpha and thus requires special attention and monitoring.

Figure 1

Overview of structural models of the spike protein of SARS-CoV-2 including mutation locations compared to the wild type. One of the trimer chains is shown as a transparent surface with the RBD domain on top of the spike protein. (a) Delta variant, mutation locations are shown as yellow spheres. (b) Omicron variant, mutation locations are shown as blue spheres. The top box shows a zoom to the RBD with the calculated Halo point cloud of the RBD.

Figure 2

Surface representation of Halo difference point clouds aiming at pairwise spike VOC RBD comparisons. (a) Each difference Halo_ij was calculated by subtracting Halo field values of the variant associated with column j from Halo field values of the variant associated with row i. Upper triangle: hydrophobicity difference Halos, difference values are scaled and colored from red (− 0.33) to blue (+ 0.33), where white (= 0) corresponds to zero difference. Lower triangle: electrostatics Halo differences with values colored from red (− 1.0) to blue (+ 1.0). Diagonal: binding interfaces of spike RBD variants in complex with hACE2. (b) WT vs. Omicron hydrophobicity difference field. (c) WT vs. Omicron electrostatics difference field. (d) Omicron RBD-hACE binding interface revealing an additional H bond between spike R493 and hACE2 E35.

Figure 3

Empirical scoring function (ESF) development. (a) Optimization of run parameters, time range and number of replicates. (b) Binding energy convergence (rank-swap frequency and average cumulative energies with standard deviation range) vs. number of MD replicates. (c) Predicted (model fitting/cross-validation and VOC prediction) vs. experimental binding affinities of a 43 variants training set plus available VOCs calculated for hACE2 residues in a 5 Å vicinity of the spike RBD (brown colored region in embedded graphic). (d) Consensus fraction between predicted and experimental top N variants.