UC Riverside

Understanding how highly symmetric, robust, monodisperse protein nano-cages self-assemblecan have major applications in various areas of bio-nanotechnology, such as drug delivery, biomedical imaging, and gene therapy. Among all the protein nano-cages, the viral shells have in particular received a lot of attention because of their abundance in nature with members infecting all kingdoms of life. The simplest viruses are made of a genome (RNA or DNA) and a protein shell called the capsid. The dissertation can be separated into two parts. The first part focuses on the equilibrium structure of nano cages. Using Monte Carlo simulation, we obtain global minimum energy structures in the absence and presence of genome. Our results suggest that the physical properties including the spontaneous curvature, flexibility, and bending rigidity of coat proteins are sufficient to predict the size, symmetry, and shape selectivity of the assembly products in the absence of genome. We find that in the presence of the genome, cargo-coat protein interactions also impact the structure and stability of the viral structures. We show that the equilibrium shells encapsidating small globular nucleic acid cargo can be assembled into non-icosahedral structures, which have been observed in experiments involving small segments of RNA. However, increasing the size of the genome the equilibrium structure switches to icosahedral structures.

In the second part, we study the kinetic pathways of assembly of virus coat proteins around the genome. Our calculations show that the non-icosahedral structures assembling around small genomes are strained and less stable than icosahedral ones. Monitoring the assembly pathways of proteins shell, we find that the strained non-icosahedral structures can easily be split into fragments along stress lines and be re-assembled into the stable native icosahedral shells if the larger wild-type genome becomes available. We also present our results corresponding to two different assembly mechanisms: en masse assembly and the nucleation and growth pathway. Using Monte Carlo simulations, we specifically elucidate the role of elastic energy in the disorder-order transition in icosahedral viruses formed through both mechanisms. Self-assembly experiments on a model icosahedral plant virus show a disorder−order transition occurs under physiological conditions upon an increase in capsid protein concentrations. We use Monte Carlo simulations to explain this disorder−order transition and find that, as the shell grows, the structures of disordered intermediates in which the distribution of pentamers do not belong to the icosahedral subgroups become energetically so unfavorable that the caps can easily dissociate and reassemble, overcoming the energy barriers for the formation of perfect icosahedral shells. In addition, we monitor the growth of capsids under the condition that nucleation and growth is the dominant pathway and show that the key for the disorder−order transition in both en masse and nucleation and growth pathways lies in the strength of elastic energy compared to the other forces in the system including protein−protein interactions and the chemical potential of free subunits. Our findings explain, at least in part, why perfect virions with icosahedral order form under different conditions including physiological ones.