How many trimers? Modeling influenza virus fusion yields a minimum aggregate size of six trimers, three of which are fusogenic

摘要

Conflicting reports in leading journals have indicated the minimum number of influenzahemagglutinin (HA) trimers required for fusion to be between one and eight. Interestingly, thedata in these reports are either almost identical, or can be transformed to be directly comparable.Different statistical or phenomenological models, however, were used to analyze these data,resulting in the varied interpretations. In an attempt to resolve this contradiction, we use PABM,a brane calculus we recently introduced, enabling an algorithmic systems biology approach thatallows the problem to be modeled in a manner following a biological logic. Since a scalablePABM executor is still under development, we sufficiently simplified the fusion modeland analyzed it using the model checker, PRISM. We validated the model against olderHA-expressing cell-to-cell fusion data using the same parameters with the exception of three,namely HA and sialic acid (SA) surface densities and the aggregation rate, which were expectedto be different as a result of the difference in the experimental setup. Results are consistent withthe interpretation that a minimum aggregate size of six HA trimers, of which three undergo aconformational change to become fusogenic, is required for fusion. Of these three, two are free,while one is bound. Finally, we determined the effects of varying the SA surface density andshowed that only a limited range of densities permit fusion. Our results demonstrate the potentialof modeling in providing more precise interpretations of data.