A modular molecular framework for quickly estimating the binding affinity of the spike protein of SARS-CoV-2 variants for ACE2, in presence of mutations at the spike receptor binding domain

Abstract

The rapid spread of new SARS-CoV-2 variants needs the development of rapid tools for predicting the affinity of the mutated proteins responsible for the infection, i.e., the SARS-CoV-2 spike protein, for the human ACE2 receptor, aiming to understand if a variant can be more efficient in invading host cells. Here we show how our computational pipeline, previously used for studying SARS-CoV-2 spike receptor-binding domain (RBD)/ACE2 interactions and pre-/post-fusion conformational changes, can be used for predicting binding affinities of the human ACE2 receptor for the spike protein RBD of the characterized infectious variants of concern/interest B.1.1.7-UK (carrying the mutations N501Y, S494P, E484K at the RBD), P.1-Japan/Brazil (RBD mutations: K417N/T, E484K, N501Y), B.1.351-South Africa (RBD mutations: K417N, E484K, N501Y), B.1.427/B.1.429-California (RBD mutations: L452R), the B.1.141 variant (RBD mutations: N439K), and the recent B.1.617.1-India (RBD mutations: L452R; E484Q) and the B.1.620 (RBD mutations: S477N; E484K). Furthermore, we searched for ACE2 structurally related proteins that might be involved in interactions with the SARS-CoV-2 spike protein, in those tissues showing low ACE2 expression, revealing two new proteins, THOP1 and NLN, deserving to be investigated for their possible inclusion in the group of host-cell entry factors responsible for host-cell SARS-CoV-2 invasion and immunity response.

Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2

“…Evolution of the SARS-COV-2 spike protein has selected for increased transmissibility, for example by increased affinity for host cells (8), with the emergence and then dominance of many new variants of concern (VOC) including Alpha, B.1.1.7; Beta, B.1.351; Gamma, P.1; Delta, B.1.617.2 (9) and most recently, Omicron, B.1.1.529 (WHO) that impact the neutralization efficacy of antibodies generated against the spike antigen of earlier strains (10). This includes profound escape from neutralization by some mAbs (11)(12)(13)(14)(15) and significant loss of neutralization activity of convalescent sera (13,16,17) and of humoral responses to first generation vaccines (12,18,19) reviewed in (10).…”

A high-affinity aptamer with base-appended base-modified DNA bound to isolated authentic SARS-CoV-2 strains wild-type and B.1.617.2 (delta variant)

“…Residue 452 is located in a “hull” portion, while residue 478 is located in the outer loop region (PDB entry number: 6m0j, [ 35 ]). Based on the modeling results of previous report [ 36 ], the replacement of residue 452 may cause to reduce the aptamer binding by steric effect or re-arrangement of the small beta-sheet. Even though the aptamer binding signal to B.1.617.2 is decreased slightly compared to wild-type, it was able to bind all examined variants of SARS-CoV-2 and not to HCoV-OC43 at all that has distinct RBD ( Fig.…”