Computational modelling of flavivirus dynamics: The ins and outs

Abstract

Enveloped viruses such as the flaviviruses represent a significant burden to human health around the world, with hundreds of millions of people each year affected by dengue alone. In an effort to improve our understanding of the molecular basis for the infective mechanisms of these viruses, extensive computational modelling approaches have been applied to elucidate their conformational dynamics. Multiscale protocols have been developed to simulate flavivirus envelopes in close accordance with biophysical data, in particular derived from cryo-electron microscopy, enabling high-resolution refinement of their structures and elucidation of the conformational changes associated with adaptation both to host environments and to immunological factors such as antibodies. Likewise, integrative modelling efforts combining data from biophysical experiments and from genome sequencing with chemical modification are providing unparalleled insights into the architecture of the previously unresolved nucleocapsid complex. Collectively, this work provides the basis for the future rational design of new antiviral therapeutics and vaccine development strategies targeting enveloped viruses.

Two decades of Martini: Better beads, broader scope

“…Although we are not there yet, progress toward this challenging goal is being made by many groups. For instance, simulations of entire viruses have already been reported, [411][412][413][414] and protocols for setting up such simulations are becoming available. 413,415,416 An advantage of using a CG model is that many conditions can be probed, in particular with placing reasonable amounts of lipids in both leaflets and an appropriate amount of interior solvent, including ions.…”

“…For instance, simulations of entire viruses have already been reported, [411][412][413][414] and protocols for setting up such simulations are becoming available. 413,415,416 An advantage of using a CG model is that many conditions can be probed, in particular with placing reasonable amounts of lipids in both leaflets and an appropriate amount of interior solvent, including ions. Initial choices often lead to instabilities which only become apparent after many microseconds of simulation.…”

Pragmatic Coarse-Graining of Proteins: Models and Applications

“…In one of these studies, Pezeshkian et al studied 100 nm diameter SARS-CoV-2 envelope structures containing over 2000 proteins for 4 μs, allowing the observation of significant molecular rearrangements. The 50 nm diameter Dengue viral envelope, containing over 180 proteins, has also been probed …”

“…The 50 nm diameter Dengue viral envelope, containing over 180 proteins, has also been probed. 232 IDPs have also been explored with Martini. While it was found that Martini underestimates the global dimensions of IDPs, when combined with an increase in the strength of protein−water interactions it results in conformational ensembles in good agreement with experiments 233,234 (Figure 2, c).…”

Multiscale Modeling of Hepatitis B Virus Capsid Assembly and its Dimorphism

“…Computational models can reveal details of the assembly process that are not accessible to experiments. However, while atomistic and near-atomistic simulations have revealed the dynamics of complete viruses [1,[37][38][39][40][41][42][43], the long timescales (ms-hours) prohibit simulating capsid assembly with atomic-resolution, ex-cept for specific steps [44,45]. Therefore, coarsegrained models have been used to study the assembly dynamics of icosahedral shells [8,.…”