  Icosahedral viruses have their infectious genome encapsulated by a shell
assembled by a multiscale process, starting from an integer multiple of 60
viral capsid or coat protein (VP) monomers.
  We predict and validate inter-atomic hotspot interactions between VP monomers
that are important for the assembly of 3 icosahedral viral capsids: Adeno
Associated Virus serotype 2 (AAV2) and Minute Virus of Mice (MVM), both T=1
single stranded DNA viruses, and Bromo Mosaic Virus (BMV), a T=3 single
stranded RNA virus. Experimental validation is by in-vitro, site-directed
mutagenesis data found in literature.
  We combine ab-initio predictions at two scales: at the interface-scale, we
predict the importance (cruciality) of an interaction for successful
subassembly across each interface between VP monomers; and at the capsid-scale,
we predict the cruciality of an interface for successful capsid assembly.
  At the interface-scale, we measure cruciality by changes in the capsid
free-energy landscape partition function when an interaction is removed. The
partition function computation uses atlases of interface subassembly
landscapes, rapidly generated by a novel geometric method and curated
opensource software EASAL (efficient atlasing and search of assembly
landscapes). At the capsid-scale, cruciality of an interface for successful
assembly of the capsid is based on combinatorial entropy.
  Our study goes from resource-light, multiscale computational predictions of
crucial hotspot inter-atomic interactions to validation using data on
site-directed mutagenesis' effect on capsid assembly. By reliably and rapidly
narrowing down target interactions, (no more than 1.5 hours per interface on a
laptop with Intel Core i5-2500K 3.2Ghz CPU and 8GB of RAM) our predictions can
inform and reduce time-consuming in-vitro and in-vivo experiments, or more
computationally intensive in-silico analyses.
