The hepatitis B virus capsid represents a promising therapeutic target. Experiments suggest the capsid must be flexible to function; however, capsid structure and dynamics have not been thoroughly characterized in the absence of icosahedral symmetry constraints. Here, all-atom molecular dynamics simulations are leveraged to investigate the capsid without symmetry bias, enabling study of capsid flexibility and its implications for biological function and cryo-EM resolution limits. Simulation results confirm flexibility and reveal a propensity for asymmetric distortion. The capsid’s influence on ionic species suggests a mechanism for modulating the display of cellular signals and implicates the capsid’s triangular pores as the location of signal exposure. A theoretical image reconstruction performed using simulated conformations indicates how capsid flexibility may limit the resolution of cryo-EM. Overall, the present work provides functional insight beyond what is accessible to experimental methods and raises important considerations regarding asymmetry in structural studies of icosahedral virus capsids.

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.

The representation of protein 3D structures in the now-ubiquitous ribbon format profoundly aids in simplifying the visualization of protein structures, enabling rapid recognition of similarities and differences between protein domains. While ribbon representations can also be convenient for illustrating the 3D features of regular repeating polysaccharide structures ( Pérez et al. 2015; Kuttel et al. 2006), the lack of highly ordered structural motifs in most oligosaccharides (glycans) attenuates the information content of such representations. The widely accepted 2D glycan symbol nomenclature developed in the 2nd edition of the Essentials of Glycobiology textbook ( Varki et al. 1999), quickly communicates glycan sequence according to a system of shapes and colors for monosaccharides, and has recently been expanded and renamed the Symbol Nomenclature for Glycans (SNFG) ( Varki et al. 2015). However, it does not convey an appreciation for the 3D structure of the glycans. Attempts to incorporate early versions of such symbols into glycan 3D structures have been proposed ( Pendrill et al. 2013), but to date the most common representations remain formats in which the atoms of the glycan are simply colored according to the SNFG scheme ( Pérez et al. 2015).

The rise of the computer as a powerful tool for model building and refinement has revolutionized the field of structure determination for large biomolecular systems. Despite the wide availability of robust experimental methods capable of resolving structural details across a range of spatiotemporal resolutions, computational hybrid methods have the unique ability to integrate the diverse data from multimodal techniques such as X-ray crystallography and electron microscopy into consistent, fully atomistic structures. Here, commonly employed strategies for computational real-space structural refinement are reviewed, and their specific applications are illustrated for several large macromolecular complexes: ribosome, virus capsids, chemosensory array, and photosynthetic chromatophore. The increasingly important role of computational methods in large-scale structural refinement, along with current and future challenges, is discussed.