Pathways for Virus Assembly around Nucleic Acids

Abstract

Understanding the pathways by which viral capsid proteins assemble around their genomes could identify key intermediates as potential drug targets. In this work we use computer simulations to characterize assembly over a wide range of capsid protein-protein interaction strengths and solution ionic strengths. We find that assembly pathways can be categorized into two classes, in which intermediates are either predominantly ordered or disordered. Our results suggest that estimating the protein-protein and the protein-genome binding affinities may be sufficient to predict which pathway occurs. Furthermore, the calculated phase diagrams suggest that knowledge of the dominant assembly pathway and its relationship to control parameters could identify optimal strategies to thwart or redirect assembly to block infection. Finally, analysis of simulation trajectories suggests that the two classes of assembly pathways can be distinguished in single molecule fluorescence correlation spectroscopy or bulk time resolved small angle x-ray scattering experiments.

Molecular dynamics simulations of large macromolecular complexes

“…However, the rate at which assembly occurs prevents a molecular-level description of the process by experimental means, making it an attractive task for computational modeling. The virus assembly kinetics and pathways can be computationally determined using stochastic kinetics [30], elastic networks [31], simulation-based data fitting [32], and CGMD simulations [23, 33, 30, 34]. In fact, by means of CGMD simulations, optimal configuration of the viral genome has been shown to be essential for proper assembly of the capsid [23, 33].…”

“…The virus assembly kinetics and pathways can be computationally determined using stochastic kinetics [30], elastic networks [31], simulation-based data fitting [32], and CGMD simulations [23, 33, 30, 34]. In fact, by means of CGMD simulations, optimal configuration of the viral genome has been shown to be essential for proper assembly of the capsid [23, 33]. In the particular case of simian virus 40 (SV40), two pathways have been observed during assembly, with each of the pathways sampling different intermediate states depending on the strength of both ionic solution and protein-protein interactions [23]* 4 .…”

“…In fact, by means of CGMD simulations, optimal configuration of the viral genome has been shown to be essential for proper assembly of the capsid [23, 33]. In the particular case of simian virus 40 (SV40), two pathways have been observed during assembly, with each of the pathways sampling different intermediate states depending on the strength of both ionic solution and protein-protein interactions [23]* 4 . Coarse-grained simulations have also been performed to investigate the self-assembly process of the HIV-1 mature capsid [35, 36, 1], allowing the identification of a trimer-of-dimers structure as a fundamental step during assembly of hexagonal lattices in a crowded enviroment [35, 36].…”

“…The viruses were arranged in the order of increasing size with the capsid diameters given in parentheses : STMV (17 nm) [20], poliovirus (32 nm) [22], RHDV (43 nm) [15], SV40 (49 nm) [23], and HIV-1 (70–100 nm) [1]. For size comparison, HIV-1 protease, one of the most studied enzymes, is shown at the bottom right.…”

“… 4 [23]* This paper describes various assembly pathways of a non-enveloped DNA virus under different ionic concentrations by using coarse-grained Brownian dynamics simulation. …”