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Flexweb Highlights May, 2006
Stochastic kinetics of viral capsid assembly based on detailed protein structures.
Martin Hemberg, Sophia N. Yaliraki, and
Mauricio Barahona(2006) Biophys. J., 90. 
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The lethality of viruses stems from their simplicity as organisms. Viruses consist of genetic material enveloped by a protective protein shell, the capsid. In fact, the viral genetic material encodes the sequence of the capsid proteins. Viruses hijack the transcription machinery of the infected cell to produce copies of the capsid proteins which then assemble into highly symmetric structures that enclose the genetic material. In this manner new viruses are created to continue spreading the disease.  Transitions between oligomers of size 6 or smaller that occur in high frequecy. The surface of the capsid is represented schematically, and the different oligmers are shown as shaded regions within each schematic. Dashed lines between oligomeric states indicate dissociation reactions. The thickness of each line is proportional to the logarithm of the frequency of the reaction. Assembly of the capsid is a crucial step in the virus life cycle and has been suggested as a target for anti-viral drugs. In this paper, we present a modular and extensible computational framework for the simulation of the assembly of icosahedral viral capsids. Our model is built from the bottom upwards, starting with detailed structural data of capsid proteins obtained from crystallographic experiments from the database VIPER. Currently, full Molecular Dynamics simulations of the assembly of such all-atom descriptions are infeasible. Therefore we obtain coarse-grained, computationally tractable models of the protein oligomers through a flexibility analysis of the protein aggregates, which is performed in a highly efficient manner by FIRST. 
Coarse-grained description of a capsid protein structure. The
capsid of Southern Bean Mosaic Virus consists of 60 copies of a
single protein (PDB code: 1stm). The atomic structure (A) is
analyzed with the software FIRST to produce a rigid cluster
decomposition (B). The rigid clusters are treated as domains (C)
that are used to compute dissociation rates in the capsid assembly
process.
The reduced description of the oligomers is used to simulate the kinetics of the assembly process. The aim is to find the pathways and the intermediates through which the capsid is formed. For this purpose we use a kinetic Monte Carlo algorithm: a version of Gillespie's algorithm modified to include the effects of water solution, diffusion and geometric form factors in the aggregation process. The reduced protein representations are also key to the description of the dissociation events (i.e., when an oligomer breaks into smaller parts) within the framework of transition state theory. Because the model is based on biophysical considerations it has relatively few parameters with direct physical meaning. We illustrate the methodology through two viruses that lead to distinct assembly pathways. Importantly, the framework does not assume which intermediates will be important; rather, these features emerge in a bottom-up fashion from the structural data. |
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