All-Atom Molecular Dynamics of Virus Capsids as Drug Targets

Abstract

Virus capsids are protein shells that package the viral genome. Although their morphology and biological functions can vary markedly, capsids often play critical roles in regulating viral infection pathways. A detailed knowledge of virus capsids, including their dynamic structure, interactions with cellular factors, and the specific roles that they play in the replication cycle, is imperative for the development of antiviral therapeutics. The following Perspective introduces an emerging area of computational biology that focuses on the dynamics of virus capsids and capsid–protein assemblies, with particular emphasis on the effects of small-molecule drug binding on capsid structure, stability, and allosteric pathways. When performed at chemical detail, molecular dynamics simulations can reveal subtle changes in virus capsids induced by drug molecules a fraction of their size. Here, the current challenges of performing all-atom capsid–drug simulations are discussed, along with an outlook on the applicability of virus capsid simulations to reveal novel drug targets.

All-Atom Molecular Dynamics Simulations of Entire Virus Capsid Reveal the Role of Ion Distribution in Capsid’s Stability

“…In addition, experiments do not resolve some parts of the viral particles (typically flexible or disordered) that can be important for the structure and the dynamics of the virus. 1,2 …”

Agent‐Based Modeling in Molecular Systems Biology

“…A comparison between the size of the system of interest and the timescales achievable by different molecular computational modeling techniques including molecular dynamics (MD), coarse‐grained MD, Brownian dynamics, agent‐based modeling . Examples of studies employing these approaches are provided as references.…”

All-atom virus simulations

“…Capsids generally represent the largest protein components of virus structures, and simulations of intact capsids have accounted for the most substantial all-atom virus simulations yet published [106, 2]. Work by Perilla et al has clearly demonstrated the need for chemical detail to facilitate accurate simulation studies of virus capsids as drug targets [107]. …”

“…The results of the work implicate the triangular pores as the extrusion site of the capsid’s carboxy-terminal domain tails, which contain cellular signals, and suggest a mechanism by which the capsid could modulate signal exposure based on tail phosphorylation. Simulations have also been used to investigate the effects of small-molecule drugs on HBV capsid morphology [107] and to determine the structural basis for enhanced assembly and drug resistance in HBV capsid mutants [117]. …”