Distinguishing Reversible from Irreversible Virus Capsid Assembly

Abstract

Summary-Capsids of spherical viruses may be constructed from hundreds or thousands of copies of the major capsid protein(s). These assembly reactions are poorly understood. In this communication we consider the predicted behavior for assembly where the component reactions have weak association energy and are reversible and compare them to essentially irreversible reactions. The comparisons are based on mass action calculations and the behavior predicted from kinetic simulations where assembly is described as a cascade of low order reactions. Reversible reactions are characterized by a pseudo-critical concentration whereas irreversible reactions consumed all free subunits. Irreversible reactions are more susceptible to kinetic traps comprised of numerous small intermediates. In the case where only the ultimate step is irreversible, very low concentrations of intermediates slow the completion of the reaction so that overall it closely matches the predictions for the reversible reactions that make up the majority of the cascade. Data in the literature strongly support the hypothesis that most viruses are held together by many weak interactions. Keywordsvirus assembly; protein polymerization; kinetics; energy surfaceThe capsid of a spherical virus is a protein complex. It may have roles in intra-and extracellular trafficking, protecting and delivering the virus' nucleic acid, and even nucleic acid metabolism. Generally, but not always, spherical capsids are constructed with icosahedral symmetry, which requires that they be constructed from multiples of 60 subunits. Analytical descriptions of virus assembly run the gamut from coarse-grained simulations, 1; 2 to defining preferred assembly paths, 3; 4; 5; 6 to master equation/kinetic simulations of essentially infinite populations. 7; 8; 9; 10 Relating such models to real viruses requires formulation of constraints based on experimental studies. Here we examine how to distinguish between reversible and irreversible assembly reactions, and how to estimate association energy where the reactions are reversible.The case where all reactions are reversible is well established but necessary background. 11 Assuming the assembly reaction equilibrates, the law of mass action dictates a relationship between free capsid protein (Cp) and assembled Capsid comprised of N copies of Cp: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Accesswhere (Nc/2) is the number of intersubunit contacts holding the capsid together and (d N-1 /N) is reaction degeneracy. RT is the universal gas constant multiplied by temperature. For the system investigated in th...

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