Beyond Binding Affinity: The Kinetic-Compatibility Hypothesis for Nipah Virus Neutralization

Nipah virus (40-75% fatality) has no approved treatments. Its highly dynamic fusion (F) protein presents a severe challenge for static binder design. We analyzed 1,194 validated computational binders, focusing on 22 functionally tested candidates (8 neutralizers, 14 non-neutralizers) to identify features associated with live-virus neutralization. We initially hypothesized that maximizing binding affinity would be the primary driver of success. However, we observed an affinity-neutralization mismatch: higher static affinity did not stratify neutralizers from non-neutralizers, and ultra-tight static affinity did not correlate with functional success. We found that successful neutralizers were instead enriched for specific architectural patterns, including compu-tational structural flexibility and terminal sequence motifs. These findings motivate a "Kinetic Compatibility Hypothesis," suggesting that neutralization may require a state-dependent, multi-feature profile rather than maximum affinity alone. Further-more, we report exploratory developability associations--such as a 0.48-0.55 amyloid propensity "sweet spot" and secondary structure constraints--specific to the 15 kDa miniprotein scaffolds in this dataset. This 10-point framework integrates empirical sequence data with Orbions Astra ML model suite predictions to propose an exploratory lead-triage heuristic, though it does not yet definitively prove mechanism.