4 research outputs found
Hierarchical Order Parameters for Macromolecular Assembly Simulations. 1. Construction and Dynamical Properties of Order Parameters
Macromolecular assemblies often display a hierarchical
organization
of macromolecules or their subassemblies. To model this, we have formulated
a space warping method that enables capturing overall macromolecular
structure and dynamics via a set of coarse-grained order parameters
(OPs). This article is the first of two describing the construction
and computational implementation of an additional class of OPs that
has built into them the hierarchical architecture of macromolecular
assemblies. To accomplish this, first, the system is divided into
subsystems, each of which is described via a representative set of
OPs. Then, a global set of variables is constructed from these subsystem-centered
OPs to capture overall system organization. Dynamical properties of
the resulting OPs are compared to those of our previous nonhierarchical
ones, and implied conceptual and computational advantages are discussed
for a 100 ns, 2 million atom solvated human Papillomavirus-like particle
simulation. In the second article, the hierarchical OPs are shown
to enable a multiscale analysis that starts with the <i>N</i>-atom Liouville equation and yields rigorous Langevin equations of
stochastic OP dynamics. The latter is demonstrated via a force-field-based
simulation algorithm that probes key structural transition pathways,
simultaneously accounting for all-atom details and overall structure
Space Warping Order Parameters and Symmetry: Application to Multiscale Simulation of Macromolecular Assemblies
Coarse-grained features of macromolecular assemblies
are understood
via a set of order parameters (OPs) constructed in terms of their
all-atom configuration. OPs are shown to be slowly changing in time
and capture the large-scale spatial features of macromolecular assemblies.
The relationship of these variables to the classic notion of OPs based
on symmetry breaking phase transitions is discussed. OPs based on
space warping transformations are analyzed in detail as they naturally
provide a connection between overall structure of an assembly and
all-atom configuration. These OPs serve as the basis of a multiscale
analysis that yields Langevin equations for OP dynamics. In this context,
the characteristics of OPs and PCA modes are compared. The OPs enable
efficient all-atom multiscale simulations of the dynamics of macromolecular
assemblies in response to changes in microenvironmental conditions,
as demonstrated on the structural transitions of cowpea chlorotic
mottle virus capsid (CCMV) and RNA of the satellite tobacco mosaic
virus (STMV)
Early Stage P22 Viral Capsid Self-Assembly Mediated by Scaffolding Protein: Atom-Resolved Model and Molecular Dynamics Simulation
Molecular
dynamics simulation of an atom-resolved bacteriophage
P22 capsid model is used to delineate the underlying mechanism of
early stage P22 self-assembly. A dimer formed by the C-terminal fragment
of scaffolding protein with a new conformation is demonstrated to
catalyze capsomer (hexamer and pentamer) aggregation efficiently.
Effects of scaffolding protein/coat protein binding patterns and scaffolding
protein concentration on efficiency, fidelity, and capsid curvature
of P22 self-assembly are identified
Omniligase-1-Mediated Phage-Peptide Library Modification and Insulin Engineering
Chemical and enzymatic modifications
of peptide-displayed libraries
have been successfully employed to expand the phage display library.
However, the requirement of specific epitopes and scaffolds has limited
the scope of protein engineering using phage display. In this study,
we present a novel approach utilizing omniligase-1-mediated selective
and specific ligation on the phage pIII protein, offering a high conversion
rate and compatibility with commercially available phage libraries.
We applied this method to perform high-throughput engineering of insulin
analogues with randomized B chain C-terminal regions. Insulin analogues
with different B chain C-terminal segments were selected and exhibited
biological activity equivalent to that of human insulin. Molecular
dynamics studies of insulin analogues revealed a novel interaction
between the insulin B27 residue and insulin receptor L1 domain. In
summary, our findings highlight the potential of omniligase-1-mediated
phage display in the development and screening of disulfide-rich peptides
and proteins. This approach holds promise for the creation of novel
insulin analogues with enhanced therapeutic properties and exhibits
potential for the development of other therapeutic compounds