Molecular frustration: a hypothesis for regulation of viral infections

Viral infections are directional; the mechanisms of assembly and disassembly are distinct and coordinated.Molecular frustration describes the coexistence of alternative states of a macromolecular system where all favourable interactions cannot be satisfied simultaneously.We hypothesize that molecular frustration of the coat proteins and their complexes with the genome in bacteriophage MS2 accounts for regulation of assembly and disassembly during infection.We therefore hypothesize that the same phenomenon may also underlie the directionality of other viral infections, for example, how cellular cofactors regulate infection by HIV. The recent revolution in imaging techniques and results from RNA footprinting in situ reveal how the bacteriophage MS2 genome regulates both particle assembly and genome release. We have proposed a model in which multiple packaging signal (PS) RNA-coat protein (CP) contacts orchestrate different stages of a viral life cycle. Programmed formation and release of specific PS contacts with CP regulates viral particle assembly and genome uncoating during cell entry. We hypothesize that molecular frustration, a concept introduced to understand protein folding, can be used to better rationalize how PSs function in both particle assembly and genome release. More broadly this concept may explain the directionality of viral life cycles, for example, the roles of host cofactors in HIV infection. We propose that this is a universal principle in virology that explains mechanisms of host–virus interaction and suggests diverse therapeutic interventions. The recent revolution in imaging techniques and results from RNA footprinting in situ reveal how the bacteriophage MS2 genome regulates both particle assembly and genome release. We have proposed a model in which multiple packaging signal (PS) RNA-coat protein (CP) contacts orchestrate different stages of a viral life cycle. Programmed formation and release of specific PS contacts with CP regulates viral particle assembly and genome uncoating during cell entry. We hypothesize that molecular frustration, a concept introduced to understand protein folding, can be used to better rationalize how PSs function in both particle assembly and genome release. More broadly this concept may explain the directionality of viral life cycles, for example, the roles of host cofactors in HIV infection. We propose that this is a universal principle in virology that explains mechanisms of host–virus interaction and