Structural basis for biologically relevant mechanical stiffening of a virus capsid by cavity-creating or spacefilling mutations

Abstract

Recent studies reveal that the mechanical properties of virus particles may have been shaped by evolution to facilitate virus survival. Manipulation of the mechanical behavior of virus capsids is leading to a better understanding of viral infection, and to the development of virus-based nanoparticles with improved mechanical properties for nanotechnological applications. In the minute virus of mice (MVM), deleterious mutations around capsid pores involved in infection-related translocation events invariably increased local mechanical stiffness and interfered with pore-associated dynamics. To provide atomic-resolution insights into biologically relevant changes in virus capsid mechanics, we have determined by X-ray crystallography the structural effects of deleterious, mechanically stiffening mutations around the capsid pores. Data show that the cavity-creating N170A mutation at the pore wall does not induce any dramatic structural change around the pores, but instead generates subtle rearrangements that propagate throughout the capsid, resulting in a more compact, less flexible structure. Analysis of the spacefilling L172W mutation revealed the same relationship between increased stiffness and compacted capsid structure. Implications for understanding connections between virus mechanics, structure, dynamics and infectivity, and for engineering modified virus-based nanoparticles, are discussed.

Structural determinants of mechanical resistance against breakage of a virus-based protein nanoparticle at a resolution of single amino acids

“…For capsid mutants F55A, N170A, N554A the difference in W t relative to the wt (ΔW mut-wt t = −23% to −38%) was statistically significant; for the other mutants the difference could not be statistically validated (Table 4). As single amino acid substitutions may have no substantial effect on the overall structure of the particle, 49 similar values for W a may be assumed for the wt capsid and any mutant, and ΔW mut-wt t values (Fig. 5A) may depend only on…”

“…[26][27][28][29][41][42][43] In particular, our group is using AFM to provide insights into the relationships between the fine structure of model virus particles, their mechanical properties, and their function. [44][45][46][47][48][49][50] By exploring the effects on a certain mechanical property (such as stiffness) of small structural alterations in the virus particle by single mutations introduced by protein engineering, knowledge about the specific chemical groups and interactions that determine that property can be acquired. [45][46][47][48][49][50] A particularly suited model for these studies is the icosahedral capsid of the minute virus of mice (MVM).…”

“…[44][45][46][47][48][49][50] By exploring the effects on a certain mechanical property (such as stiffness) of small structural alterations in the virus particle by single mutations introduced by protein engineering, knowledge about the specific chemical groups and interactions that determine that property can be acquired. [45][46][47][48][49][50] A particularly suited model for these studies is the icosahedral capsid of the minute virus of mice (MVM). 51,52 The MVM capsid ( Fig.…”

“…48 This effect was specific, as other side chains (generally located in solvent-exposed protein loops) had a minor or insignificant role in determining capsid stiffness. Individual substitutions of other amino acid residues surrounding pores or cavities in the MVM capsid 46,47,49 or in other viral particles 50,[55][56][57] had also stiffening effects.…”

Theoretical Analysis of the Induction of Forced Resonance Mechanical Oscillations to Virus Particles by Microwave Irradiation:Prospects as an Anti-virus Modality

“…Also, Elasticity Theory methods applied to draw conclusions on the mechanical properties of virus particles 4 . Electric charge distributions of virus have been also studied by several researchers 5,6,7,8,9 .…”