Evaluation of all-atom force fields in viral capsid simulations and properties

We investigate six AMBER and CHARMM force fields for molecular dynamics simulations of viral capsids. Out of the force fields studied, we recommend CHARMM36m and CHARMM36 for future use.

Viral Phrenology

We introduce Viral Phrenology, a new scheme for understanding the genomic composition of spherical viruses based on the locations of their structural protrusions. We used icosahedral point arrays to classify 135 distinct viral capsids collected from over 600 capsids available in the VIPERdb. Using gauge points of point arrays, we found 149 unique structural protrusions. We then show how to use the locations of these protrusions to determine the genetic composition of the virus. We then show that ssDNA, dsDNA, dsRNA and ssRNA viruses use different arrangements for distributing their protrusions. We also found that Triangulation number is also partially dependent on the structural protrusions. This analysis begins to tie together Baltimore Classification and Triangulation number using point arrays.

HIV-1 capsid variability: viral exploitation and evasion of capsid-binding molecules

The HIV-1 capsid, a conical shell encasing viral nucleoprotein complexes, is involved in multiple post-entry processes during viral replication. Many host factors can directly bind to the HIV-1 capsid protein (CA) and either promote or prevent HIV-1 infection. The viral capsid is currently being explored as a novel target for therapeutic interventions. In the past few decades, significant progress has been made in our understanding of the capsid–host interactions and mechanisms of action of capsid-targeting antivirals. At the same time, a large number of different viral capsids, which derive from many HIV-1 mutants, naturally occurring variants, or diverse lentiviruses, have been characterized for their interactions with capsid-binding molecules in great detail utilizing various experimental techniques. This review provides an overview of how sequence variation in CA influences phenotypic properties of HIV-1. We will focus on sequence differences that alter capsid–host interactions and give a brief account of drug resistant mutations in CA and their mutational effects on viral phenotypes. Increased knowledge of the sequence-function relationship of CA helps us deepen our understanding of the adaptive potential of the viral capsid.

Norovirus Epidemiology and Genetic Diversity in Leipzig, Germany during 2013–2017

Globally and in all age groups, noroviruses are a main cause of gastroenteritis. To assess their local epidemiology and genetic diversity, stool samples of 7509 inpatients with gastrointestinal complaints from all age groups were analyzed. After detection of norovirus genogroup I and II RNA by real-time RT-PCR, viral capsids were genotyped by partial nucleic acid sequencing. In the case of GII.2 strains, polymerase genotypes were also assessed. Between October 2013 and September 2017, presence of norovirus RNA was shown in 611 samples (8.1%), of which 610 (99.8%) were typed successfully. Norovirus positivity rate was higher in patients aged below five years (14.8%) than in older patients (5.7%). Among the 611 norovirus positive samples, GII.4 (56.6%) strains prevailed, followed by GII.6 (11.3%), GII.3 (11.0%) and GII.2 (9.5%). The most common genogroup I (GGI) genotype was GI.3 (3.6%). In addition, rare genotypes such as GII.13, GII.14 and GII.26 were detected. Interestingly, GII.3 infections were most common in children under the age of five years. Assessment of polymerase genotypes in GII.2 viruses showed a shift from P2 to P16, with higher diversity in P2 sequences. The varying distribution of norovirus genotypes depending on season, age and setting of infection highlights the importance of frequent genotyping as a basis for vaccine development and needful adjustments.

Viral Phrenology

We introduce Viral Phrenology, a new scheme for understanding the genomic composition of spherical viruses base on the locations of their structural protrusions. We used icosahedral point arrays to classify 135 distinct viral capsids collected from over 600 capsids available in the VIPERdb. Using gauge points of point arrays, we found 149 unique structural protrusions. We then show how to use the locations of these protrusions to determine the genetic composition of the virus. We then show that ssDNA, dsDNA, dsRNA and ssRNA viruses use different arrangements for distributing their protrusions. We also found that Triangulation number is also partially dependent on the structural protrusions. This analysis begins to tie together Baltimore classification and Triangulation number using point arrays.

Dual signaling via interferon and DNA damage response elicits entrapment by giant PML nuclear bodies

ABSTRACTPML nuclear bodies (PML-NBs) are dynamic interchromosomal macromolecular complexes implicated in epigenetic regulation as well as antiviral defense. During herpesvirus infection, PML-NBs induce epigenetic silencing of viral genomes, however, this defense is antagonized by viral regulatory proteins such as IE1 of human cytomegalovirus (HCMV). Here, we show that PML-NBs undergo a drastic rearrangement into highly enlarged PML cages upon infection with IE1-deficient HCMV. Importantly, our results demonstrate that dual signaling by interferon and DNA damage response is required to elicit giant PML-NBs. DNA labeling revealed that invading HCMV genomes are entrapped inside PML-NBs and remain stably associated with PML cages in a transcriptionally repressed state. Intriguingly, by correlative light and transmission electron microscopy (EM), we observed that PML cages also entrap newly assembled viral capsids demonstrating a second defense layer in cells with incomplete first line response. Further characterization by 3D EM showed that hundreds of viral capsids are tightly packed into several layers of fibrous PML. Overall, our data indicate that giant PML-NBs arise via combined interferon and DNA damage signaling which triggers entrapment of both nucleic acids and proteinaceous components. This represents a multilayered defense strategy to act in a cytoprotective manner and to combat viral infections.

Frustrated self-assembly of non-Euclidean crystals of nanoparticles

Self-organized complex structures in nature, e.g., viral capsids, hierarchical biopolymers, and bacterial flagella, offer efficiency, adaptability, robustness, and multi-functionality. Can we program the self-assembly of three-dimensional (3D) complex structures using simple building blocks, and reach similar or higher level of sophistication in engineered materials? Here we present an analytic theory for the self-assembly of polyhedral nanoparticles (NPs) based on their crystal structures in non-Euclidean space. We show that the unavoidable geometrical frustration of these particle shapes, combined with competing attractive and repulsive interparticle interactions, lead to controllable self-assembly of structures of complex order. Applying this theory to tetrahedral NPs, we find high-yield and enantiopure self-assembly of helicoidal ribbons, exhibiting qualitative agreement with experimental observations. We expect that this theory will offer a general framework for the self-assembly of simple polyhedral building blocks into rich complex morphologies with new material capabilities such as tunable optical activity, essential for multiple emerging technologies.

Protein interface redesign facilitates the transformation of nanocage building blocks to 1D and 2D nanomaterials

Although various artificial protein nanoarchitectures have been constructed, controlling the transformation between different protein assemblies has largely been unexplored. Here, we describe an approach to realize the self-assembly transformation of dimeric building blocks by adjusting their geometric arrangement. Thermotoga maritima ferritin (TmFtn) naturally occurs as a dimer; twelve of these dimers interact with each other in a head-to-side manner to generate 24-meric hollow protein nanocage in the presence of Ca2+ or PEG. By tuning two contiguous dimeric proteins to interact in a fully or partially side-by-side fashion through protein interface redesign, we can render the self-assembly transformation of such dimeric building blocks from the protein nanocage to filament, nanorod and nanoribbon in response to multiple external stimuli. We show similar dimeric protein building blocks can generate three kinds of protein materials in a manner that highly resembles natural pentamer building blocks from viral capsids that form different protein assemblies.