Molecular Energetics In The Capsomere Of Virus-like Particle Revealed By Molecular Dynamics Simulations

Virus-like particles (VLP) are highly organized nanoparticles formed by theself-assembly of envelope and/or capsid proteins from many virus, which have greatpotential in vaccinology, gene therapy, drug delivery, and materials science. However,the application of VLP is hindered by obstacles in their design and production due tolow efficiency of self-assembly and difficulty in structural regulation. In the presentstudy, molecular dynamics (MD) simulations with all-atom models and the molecularmechanics-Poisson-Boltzmann surface area (MM-PBSA) method are employed toinvestigate the early stages of the viral assembly process and to explore molecularenergetics in VLP self-assembly. The association free energy between VP1moleculesand the key factors mediating the interactions have been investigated for betterregulation of the self-assembly process.First of all, the all-atom models of capsomere of a murine polyomavirus (MPV)VLP are constructed. Four different solutions are considered according toexperimental conditions. Thereafter, the influences of both the existence of disulfidebond and the insertion of antigen fragment on the stabilization of capsomere areexamined. The total binding free energy between VP1molecules in different solutionsare calculated by MM-PBSA analysis. Finally, the free energy decomposition for eachresidues is carried out to identify the hot spots in VP1for the formation of acapsomere in different solution conditions, which could provide molecular insightsinto the molecular mechanisms of VP1-VP1association.It is found that both low ionic strength and the intra-capsomere disulfide bond arefavorable for maintaining a stable capsomere. However, the insertion of an influenzaantigen fragment seems to lower the binding energy in the capsomere. The results offree energy decomposition using MM-PBSA analysis indicate that hydrophobicinteraction is favorable for the formation of a capsomere, while electrostaticinteraction is unfavorable. In addition, the key amino acid residues (hot spots) in VP1the formation of a capsomere in different solution conditions have been identified,including residues S132, L136, D137, H139, E138, D180, E225, H228, E235, Y239,G246, T247. F255, N257, K307. These results provided molecular insights into VLP self-assembly, which wouldbe beneficial for the design of VLP-based vaccines as well as the regulation ofsolution conditions for favorable capsomere formation.