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

<div><p>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.</p></div

Membrane transporter dimerization driven by differential lipid solvation energetics of dissociated and associated states

Over two-thirds of integral membrane proteins of known structure assemble into oligomers. Yet, the forces that drive the association of these proteins remain to be delineated, as the lipid bilayer is a solvent environment that is both structurally and chemically complex. In this study, we reveal how the lipid solvent defines the dimerization equilibrium of the CLC-ec1 C

MALTA: A calculator for estimating the coverage with shRNA, CRISPR, and cDNA libraries

Genetic screens using shRNA, CRISPR, or cDNA libraries rely on adequately transferring the library into cells for further assay. These libraries can have many different elements and each element can be present at different copy numbers within a given pooled library. Calculating how many recipient cells are needed to adequately sample all or most of the different elements within a library is important, especially if one wants to compare the outcomes of different genetic screens that rely on accurately reproducing the starting population of library-containing cells. Here we present a simple application that starts with a list of library elements and their abundance and calculates the minimum sampling number to achieve full transfer of the library to an acceptor cell population to a user-specified level of probability. Users can adjust several input parameters including designating a subpopulation over which the calculation is made. Finally, the program performs a series of Monte Carlo simulations of a user-specified number of picks to produce an empirically determined distribution of each library element. Keywords: Computation, Genetic screening, Pooled librarie

Optimization of an elastic network augmented coarse grained model to study CCMV capsid deformation.

<p>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.</p

RMSD (-carbons of core regions) distributions from simulations of isolated dimers.

<p>Open histograms: RMSDs within the monomers; shaded histograms: RMSDs of dimers. (A) atomistic simulation (400 ns); (B) CG simulation with ELNEDYN network (spring constant: 500 kJ mol⁻¹nm⁻²); (C) CG simulation with ELNEDYN network (spring constant: 200 kJ mol⁻¹nm⁻²); (D) CG simulation with IDEN elastic network.</p

Statistics of RMSD distributions of monomers and dimers.

<p>Data obtained from simulations of the free dimer (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060582#pone-0060582-g003" target="_blank"><b>Figure 3</b></a>) and the POD+CC complex (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060582#pone-0060582-g006" target="_blank"><b>Figure 6</b></a>), using the atomistic model, the CG model with ELNEDYN network with a uniform elastic network constant of 500 or 200 kJ mol⁻¹nm⁻² or the IDEN elastic network.</p