Optimization of an Elastic Network Augmented Coarse Grained Model to Study CCMV Capsid Deformation

Abstract

The major protective coat of most viruses is a highly symmetric protein capsid that forms spontaneously from many copies of identical proteins. Structural and mechanical properties of such capsids, as well as their self-assembly process, have been studied experimentally and theoretically, including modeling efforts by computer simulations on various scales. Atomistic models include specific details of local protein binding but are limited in system size and accessible time, while coarse grained (CG) models do get access to longer time and length scales but often lack the specific local interactions. Multi-scale models aim at bridging this gap by systematically connecting different levels of resolution. Here, a CG model for CCMV (Cowpea Chlorotic Mottle Virus), a virus with an icosahedral shell of 180 identical protein monomers, is developed, where parameters are derived from atomistic simulations of capsid protein dimers in aqueous solution. In particular, a new method is introduced to combine the MARTINI CG model with a supportive elastic network based on structural fluctuations of individual monomers. In the parametrization process, both network connectivity and strength are optimized. This elastic-network optimized CG model, which solely relies on atomistic data of small units (dimers), is able to correctly predict inter-protein conformational flexibility and properties of larger capsid fragments of 20 and more subunits. Furthermore, it is shown that this CG model reproduces experimental (Atomic Force Microscopy) indentation measurements of the entire viral capsid. Thus it is shown that one obvious goal for hierarchical modeling, namely predicting mechanical properties of larger protein complexes from models that are carefully parametrized on elastic properties of smaller units, is achievable.

More than the sum of its parts: Coarse-grained peptide-lipid interactions from a simple cross-parametrization

“…29 While this model handles a variety of secondary structure formation aspects very accurately, for instance, cooperativity in helix and helix-bundle folding transitions 30,31 and β-barrel formation, 32 it is not detailed enough to achieve folding of complex protein structures. However, nontrivial tertiary or quaternary folds can still be treated by adding stabilizing elastic networks, 33,34 but unstructured tails and flexible loops can now be left free to explore a meaningful phase space. The implicit-solvent CG lipid model used here 35,36 provides a similar resolution as the MARTINI force field (about three to four heavy atoms per bead).…”

CapsidMesh: atomic-detail structured mesh representation of icosahedral viral capsids and the study of their mechanical properties

“…As mentioned earlier, the mechanical response characterized through AFM nanoindentation experiments performed on the Cowpea Chlorotic Mottle Virus (CCMV) [5,22,23] have been computationally studied previously [11,12,24]. Given the amount of structural and physical information available, here we take the CCMV capsid as a test case to generate a CapsidMesh with our methodology which can then be used to study the mechanical properties of a macromolecular particle.…”

“…From a theoretical standpoint, it has also become possible to study whole viruses by molecular dynamics (MD) methods employing all-atom models [6][7][8][9]. In particular, the nanoindentation experiments performed on the Cowpea Chlorotic Mottle Virus (CCMV) [10] have been computationally studied to some depth using coarse-grain models [11], elastic network approximations [12], and topology-based self-organized polymer models [13].…”

Enhanced Sampling of Coarse-Grained Transmembrane-Peptide Structure Formation from Hydrogen-Bond Replica Exchange

“…Further applications of the model include the thermodynamics of helix-folding transitions (Bereau et al 2010 and the formation of b-barrels at the interface between virus capsid proteins (Bereau et al 2012). Though the model lacks chemical detail to fold more complex protein structures, the use of stabilizing elastic networks (e.g., Periole et al 2009;Globisch et al 2013) on parts of the protein can help explore the conformational variability of flexible segments.…”