Molecular Energetics in the Capsomere of Virus-Like Particle Revealed by Molecular Dynamics Simulations

Abstract

Virus-like particles (VLPs) are highly organized nanoparticles that have great potential in vaccinology, gene therapy, drug delivery, and materials science. However, the application of VLPs is hindered by obstacles in their design and production due to low efficiency of self-assembly. In the present study, all-atom (AA) molecular dynamics (MD) simulations coupled with the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method are utilized to examine the molecular interactions in the capsomere of a murine polyomavirus (MPV) VLP. It is found that both low ionic strength and the intracapsomere disulfide bonds are favorable for maintaining a stable capsomere. Simulation results examining the effects of solution conditions on the stabilization of a capsomere were verified by calorimetry experiments. Simulation results of free energy decomposition indicate that hydrophobic interaction is favorable for the formation of a capsomere, whereas electrostatic interaction is unfavorable. With increasing ionic strength, the dominant interaction for the stabilization of a capsomere changes from hydrophobic to electrostatic. By comprehensive analyses, the key amino acid residues (hot spots) in VP1 protein aiding formation of a capsomere in different solution conditions have been identified. These results provide molecular insights into the stabilization of building blocks for VLP and are expected to have implications in their partitioning between the correct and off-pathway reactions in VLP assembly.

Energetic Changes Caused by Antigenic Module Insertion in a Virus-Like Particle Revealed by Experiment and Molecular Dynamics Simulations

“…The system constructed is of a single modular capsomere as reported previously [23], with an additional influenza epitope module (VP1-GCN4-H190-GCN4 capsomere) as studied previously [27] denoted here as Ag-Cap, where H190 (STSADQQSLYQNADAY) is from H1N1 A/California/07/2009 influenza. The AA model of Ag-Cap was constructed using Accelrys Discovery Studio 3.0 (Accelrys, Inc., San Diego, USA), which is convenient for homology modeling.…”

“…S1 in Supporting Information. Two solution conditions including Stabilization Buffer (S3) and Assembly Buffer (S4) were considered (Table 1) [23]. The simple point charge (SPC) model is used for water molecules.…”

“…a The same solution conditions of S3 and S4 used for Cap reported previously [23] were used herein for Ag-Cap to examine the energetic changes due to antigenic module insertion.b - and + represent absence and existence of disulfide bonds, respectively.…”

“…MD simulations in the NPT ensemble were performed using GROMACS 4.5.3 package [28] (http://www.gromacs.org/) with the GROMOS96 43a1 force field, following the procedure proposed in the previous work [23]. Temperature was controlled at 310.15 K by the velocity-rescale (v-rescale) [29] method with a time constant of 0.5 ps.…”

“…In our earlier work [23], the molecular interactions in the capsomere of a murine polyomavirus (MPV) VLP has been extensively investigated. In the present study, the molecular energetics within a modular capsomere of MPV VLP designed to protect against influenza was investigated using all-atom (AA) MD simulations coupled with the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method [24],[25],[26].…”