Investigating Scaling Effects on Virus Capsid-Like Self-Assembly Using Discrete Event Simulations

Abstract

As self-assembled nanotechnology tackles increasingly complicated structures, biological self-assembly can teach us a great deal about the challenges of more complicated self-assemblies relative to the simpler systems accessible in current practice. The present study uses computer simulations of spherical assemblies inspired by virus capsids to understand the challenges artificial self-assembly systems will face as they approach biological levels of complexity. We quantify system complexity by two parameters-the total size of the completed structure in assembly monomers and the size of the first stable assembly nucleus. Simulations on a set of five model systems capturing a range of values for both parameters reveal several obstacles to extrapolating experience with simple systems to more complex ones. Assemblies of greater size result in total yields and assembly fidelities that are substantially more sensitive to the system parameters of intersubunit binding rates and to concentrations than are those of simpler assemblies. Larger nuclei partially mitigate these effects. Conversely, large assemblies have overall assembly rates with reduced sensitivity to system parameters, a feature that is also only partly mitigated by large nuclei. These changes can be partially understood by theoretical models based on nucleation processes, but such theory itself becomes less informative for the larger systems. We close with a consideration of mechanisms by which these obstacles may be overcome in actual viral systems.

Icosahedral capsid formation by capsomers and short polyions

“…19,21,23,24,34 Here, the numerical density of capsomers was approximately 830 μM (as trimers of capsid proteins), roughly 2-3 magnitudes larger than the values often used in relative studies. 19,24,36 With non-optimal associating interaction strength, i.e., ε attr = 110 kJ mol −1 Å 2 , the structural polymorphism is in fact very significant.…”

“…For example, the co-assembly can be very sensitive to ambient conditions such as pH and ionic strength. In recent years, increasing efforts have been paid to theoretical and experimental investigations of the capsid self-assembly, 14,[30][31][32][33][34][35][36][37][38][39][40] especially studies of the influence of spherical [41][42][43][44] or chain-like [45][46][47][48] cargos on the virus capsid formation.…”

Pathway Complexity of Model Virus Capsid Assembly Systems

“…[34], representing a full T ¼ 1 capsid assembly system at the monomer level. This model constructs icosahedrally symmetric 60-mers from an assembly subunit with three binding sites, two that bind to copies of one another to form pentamers of coat protein (capsomers) and one that binds copies of itself to link together capsomers to form the complete icosahedron.…”

“…Several simulation studies of capsid assembly have suggested that changing parameter values (e.g., binding free energies, concentrations or configurational tolerances of binding) so as to promote more rapid assembly can abruptly shift a system from a productive nucleation-limited assembly pathway to an unproductive pathway dominated by kinetically trapped incomplete structures [4,14,17,18,20,21,32,34]. Other studies have shown that similarly small changes in assembly conditions can shift pathways so as to alter the morphology of final assembled structures [1,14,17,18,21].…”

Self-assembly of monodisperse clusters: Dependence on target geometry

“…15 The production of functional self-assembling systems will require not only advanced synthesis techniques to produce the subunits but also a strong theoretical understanding of the self-assembly process so that appropriate designs and conditions can be chosen. Recently there has been significant progress in the theory [16][17][18][19] and simulation [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] of monodisperse self-assembly. However, these studies have mostly focused on the self-assembly of virus capsids or other protein complexes, [16][17][18][20][21][22][23][24][25][26][27][28][29][30][31][32] and so include proteinlike interactions which are more specific than those which are likely to be available in the first generation of synthetic patchy particles.…”