Unraveling the Motions behind Enterovirus 71 Uncoating

Abstract

Enterovirus 71 can be a severe pathogen in small children and immunocompromised adults. Virus uncoating is a critical step in the infection of the host cell; however, the mechanisms that control this process remain poorly understood. We applied normal mode analysis and perturbation response scanning to several complexes of the virus capsid and present a coarse-graining approach to analyze the full capsid. We show that our method offers an alternative to expressing the system as a set of rigid blocks and accounts for the interconnection between nodes within each subunit and protein interfaces across the capsid. In our coarse-grained approach, the modes associated with capsid expansion are captured in the first three nondegenerate modes and correspond to the changes observed in structural studies of the virus. We show that the resolution of the analysis may be modified without losing information on the global motions leading to uncoating. Perturbation response scanning revealed that a protomer cannot serve as a functional unit to explain deformations of the capsid. Instead, we define a pentamer as the minimum functional unit to investigate changes within the capsid. From the modal analysis and perturbation response scanning, we locate a hotspot region surrounding the fivefold axis. The range of the effect of these single, hotspot residues extend to 140 Å. The perturbation of internal capsid residues in this region displayed greatest propensity to capsid expansion, thus indicating the significant role that the RNA genome may play in triggering uncoating.

MODE-TASK: large-scale protein motion tools

“…The MODE-TASK algorithm was validated in a previous study of the Enterovirus 71 (EV71) capsid ( Ross et al , 2018 ). The EV71 capsid is icosahedral with T = 3 symmetry.…”

“…The RTB approach only captured a single dominant mode (radial expansion) for the CCMV capsid. It was suggested that the two additional modes captured by the MODE-TASK algorithm represent the local motions within a pentameric unit ( Ross et al , 2018 ).…”

“…The MODE-TASK coarse graining algorithm offers an alternative approach to the rotation-translation of blocks (RTB) method ( Durand et al , 1994 ; Tama et al , 2000 ). The algorithm was recently validated in a virus study ( Ross et al , 2018 ).…”

Integrated Computational Approaches and Tools for Allosteric Drug Discovery

“…ENM are a type of coarse-grained NMA, which can substantially reduce the computational demands to efficiently explore protein dynamics around a single energy minimum by simplifying interatomic interactions as spring-connected nodes (protein C β and/or C α atoms) [227,280,281,[281][282][283][284]. Several studies involving this approach have verified its success in identifying functionally relevant protein conformations [175,[285][286][287][288][289][290][291][292]. Further, coarse-grained NMA [293][294][295] and ENM integrated with the information-based Markovian theory of signal propagation [296][297][298][299][300][301][302][303] have provided a generalized formalism of allosteric communication pathways in proteins.…”

“…The application of ED to analyze protein behaviour mainly focuses on the dominant modes of motion, which are obtained by decomposing the covariance matrix and by ranking the eigenvectors (principal components) in descending order of the corresponding eigenvalues [292,332]. By plotting the first two or three principal components against each other, we obtain a general idea of the distribution for all generated conformations obtained from a conformational sampling experiment, as exemplified from ED analyzes for various proteins [333][334][335][336].…”