Because computational prediction deems the RBD a non-ideal binding solution unlike the residues known to be optimal in SARS-CoV, a rational designer using structure-based methods would not have produced it; the strong human-ACE2 binding is therefore best explained by natural selection, which the authors call strong evidence against purposeful manipulation.
Reasoning
If SARS-CoV-2 had been engineered to bind human ACE2, the designer would most plausibly have reproduced the residues already demonstrated (in SARS-CoV structural/mutagenesis work) to be optimal for ACE2 binding. Instead, the six SARS-CoV-2 contact residues differ from that known-optimal set (five of six differ), and computational docking predicts the interaction is ‘not ideal’ even though the virus binds hACE2 with high affinity in reality. The most parsimonious way to reach a high-affinity yet non-textbook-optimal solution is natural selection acting on a human or human-like ACE2, which explores idiosyncratic solutions rather than a pre-known optimum. Hence the RBD’s character is taken as evidence for natural selection and against deliberate design. The inference rests on the premise that a deliberate designer would have used the previously identified optimal residues, and on the reliability of the docking prediction.
Original
Because computational prediction deems the RBD a non-ideal binding solution unlike the residues known to be optimal in SARS-CoV, a rational designer using structure-based methods would not have produced it; the strong human-ACE2 binding is therefore best explained by natural selection, which the authors call strong evidence against purposeful manipulation.
Verdict — corrected (checked)
Reconstruction. Premises: (i) SARS-CoV-2’s six ACE2-contact residues differ from the set shown optimal for ACE2 binding in prior SARS-CoV work (5 of 6 differ); (ii) docking predicts the interaction is “not ideal” though real binding is high-affinity; (iii, hidden, load-bearing) an engineer of this RBD would have reproduced the previously identified optimal residues. Load-bearing step: since the RBD is not the known-optimal solution a designer would have used, it was not designed, so natural selection explains it — evidence against purposeful manipulation.
Evaluation. Conditional on premise (iii) the step goes through only for a designer working by structure-based rational design from a known optimum. But (iii) is not the sole form of engineering, and rescuing the broad conclusion requires the further premise that all deliberate manipulation is structure-based rational design — a completion-by-force premise no one would grant. Directed evolution / serial passage in humanized-ACE2 systems, standard well before 2020, selects empirically for high affinity and would produce exactly a non-textbook-optimal, “not ideal”-looking yet strongly-binding RBD — the same signature natural selection leaves. This undercutting defeater breaks the link to “against purposeful manipulation” without denying any premise. A weaker conclusion is immune: the observation argues specifically against structure-based rational design of the RBD. Corrected to that scope; the residue-comparison and the design-mode taxonomy are traced directly, author-blind.