Coarse-grained Simulations and AFM Nanoindentation Experiments on a Hepatitis B Virus Capsid

Abstract

Mechanical properties of viral capsids are key to the replication cycle of viruses, since a capsid should be stable to protect the virus from the hostile environment outside of host cells, but also needs to disassemble or otherwise release the viral genome during the infection process. Relatively little is known about mechanics of capsids and the underlying molecular mechanisms, however, valuable information is coming from capsid nanoindentation studies employing atomic force microscopy (AFM). The latter provides the force response, in particular, its dependence on the depth of indentation. Details of the corresponding capsid deformation have been studied in recent years through finite-element simulations employing continuous elastic material models. Despite interesting insights, this approach has been limited, since molecular details are not resolved and irreversible structural transitions could not be simulated. On the other hand, detailed atomistic simulations could not handle this problem either, due to the large size of the system and the long time scales involved. We have developed and tested a new shape-based coarse-grained molecular dynamics model that permits us to simulate AFM nanoindentation experiments. We applied the method to the hepatitis B virus capsid. The simulations resolved shapes of individual protein units and allowed us to reach time scales of tens of microseconds. The force response simulated is found in quantitative agreement with experiments. Irreversible deformation (failure) of capsids is observed in repeated rounds of nanoindentation, also in agreement with experiment. The simulations explain observed features of the experimental force-indentation curve, showing which molecular-level events are responsible for specific force responses, and suggesting how the capsid is deformed in the cases of reversible and irreversible indentation.