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.

B-cell epitope discovery: The first protein flexibility-based algorithm-Zika virus conserved epitope demonstration.

Antibody-antigen interaction-at antigenic local environments called B-cell epitopes-is a prominent mechanism for neutralization of infection. Effective mimicry, and display, of B-cell epitopes is key to vaccine design. Here, a physical approach is evaluated for the discovery of epitopes which evolve slowly over closely related pathogens (conserved epitopes).

Temporally Coarse-Grained All-Atom Molecular Dynamics Achieved via Stochastic Padé Approximants.

A Padé approximant scheme for realizing the discrete-time evolution of the state of a many-atom system is introduced. This temporal coarse-graining scheme accounts for the underlying Newtonian physics and avoids the need for construction of spatially coarse-grained variables. Newtonian physics is incorporated through short molecular dynamics simulations at the beginning of each of the large coarse-grained timesteps.

Amphiphile self-assembly dynamics at the solution-solid interface reveal asymmetry in head/tail desorption.

Amphiphilic alkoxybenzonitriles (ABNs) of varying chain length are studied at the solution/graphite interface to analyze dynamics of assembly. Competitive self-assembly between ABNs and alkanoic acid solvent is shown by scanning tunneling microscopy (STM) to be controlled by concentration and molecular size. Molecular dynamics (MD) simulations reveal key roles of the sub-nanosecond fundamental steps of desorption, adsorption, and on-surface motion.

Multiscale Molecular Dynamics Approach to Energy Transfer in Nanomaterials.

After local transient fluctuations are dissipated, in an energy transfer process, a system evolves to a state where the energy density field varies slowly in time relative to the dynamics of atomic collisions and vibrations. Furthermore, the energy density field remains strongly coupled to the atomic scale processes (collisions and vibrations), and it can serve as the basis of a multiscale theory of energy transfer. Here, a method is introduced to capture the long scale energy density variations as they coevolve with the atomistic state in a way that yields insights into the basic physics and implies an efficient algorithm for energy transfer simulations.

Multiscale time-dependent density functional theory: Demonstration for plasmons.

Plasmon properties are of significant interest in pure and applied nanoscience. While time-dependent density functional theory (TDDFT) can be used to study plasmons, it becomes impractical for elucidating the effect of size, geometric arrangement, and dimensionality in complex nanosystems. In this study, a new multiscale formalism that addresses this challenge is proposed.

Reverse Coarse-Graining for Equation-Free Modeling: Application to Multiscale Molecular Dynamics.

Constructing atom-resolved states from low-resolution data is of practical importance in many areas of science and engineering. This problem is addressed in this article in the context of multiscale factorization methods for molecular dynamics. These methods capture the crosstalk between atomic and coarse-grained scales arising in macromolecular systems.

Multiscale Modeling in the Clinic: Drug Design and Development.

A wide range of length and time scales are relevant to pharmacology, especially in drug development, drug design and drug delivery. Therefore, multiscale computational modeling and simulation methods and paradigms that advance the linkage of phenomena occurring at these multiple scales have become increasingly important. Multiscale approaches present in silico opportunities to advance laboratory research to bedside clinical applications in pharmaceuticals research.

Implicit Time Integration for Multiscale Molecular Dynamics Using Transcendental Padé Approximants.

Molecular dynamics systems evolve through the interplay of collective and localized disturbances. As a practical consequence, there is a restriction on the time step imposed by the broad spectrum of time scales involved. To resolve this restriction, multiscale factorization was introduced for molecular dynamics as a method that exploits the separation of time scales by coevolving the coarse-grained and atom-resolved states via Trotter factorization.

Broad spectrum assessment of the epitope fluctuation--Immunogenicity hypothesis.

Prediction of immunogenicity is a substantial barrier in vaccine design. Here, a molecular dynamics approach to assessing the immunogenicity of nanoparticles based on structure is presented. Molecular properties of epitopes on nonenveloped viral particles are quantified via a set of metrics.

Prospective on multiscale simulation of virus-like particles: Application to computer-aided vaccine design.

Simulations of virus-like particles needed for computer-aided vaccine design highlight the need for new algorithms that accelerate molecular dynamics. Such simulations via conventional molecular dynamics present a practical challenge due to the millions of atoms involved and the long timescales of the phenomena of interest. These phenomena include structural transitions, self-assembly, and interaction with a cell surface.

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.

Multiscale Factorization Method for Simulating Mesoscopic Systems with Atomic Precision.

Mesoscopic -atom systems derive their structural and dynamical properties from processes coupled across multiple scales in space and time. A multiscale method for simulating these systems in the friction dominated regime from the underlying -atom formulation is presented. The method integrates notions of multiscale analysis, Trotter factorization, and a hypothesis that the momenta conjugate to coarse-grained variables constitute a stationary process on the time scale of coarse-grained dynamics.

A multiscale variational approach to the kinetics of viscous classical liquids: the coarse-grained mean field approximation.

A closed kinetic equation for the single-particle density of a viscous simple liquid is derived using a variational method for the Liouville equation and a coarse-grained mean-field (CGMF) ansatz. The CGMF ansatz is based on the notion that during the characteristic time of deformation a given particle interacts with many others so that it experiences an average interaction. A trial function for the N-particle probability density is constructed using a multiscale perturbation method and the CGMF ansatz is applied to it.

Energy transfer between a nanosystem and its host fluid: a multiscale factorization approach.

Energy transfer between a macromolecule or supramolecular assembly and a host medium is considered from the perspective of Newton's equations and Lie-Trotter factorization. The development starts by demonstrating that the energy of the molecule evolves slowly relative to the time scale of atomic collisions-vibrations. The energy is envisioned to be a coarse-grained variable that coevolves with the rapidly fluctuating atomistic degrees of freedom.

Epitope fluctuations in the human papillomavirus are under dynamic allosteric control: a computational evaluation of a new vaccine design strategy.

The dynamic properties of the capsid of the human papillomavirus (HPV) type 16 were examined using classical molecular dynamics simulations. By systematically comparing the structural fluctuations of the capsid protein, a strong dynamic allosteric connection between the epitope containing loops and the h4 helix located more than 50 Å away is identified, which was not recognized thus far. Computer simulations show that restricting the structural fluctuations of the h4 helix is key to rigidifying the epitopes, which is thought to be required for eliciting a proper immune response.

Epitope engineering and molecular metrics of immunogenicity: a computational approach to VLP-based vaccine design.

Developing antiviral vaccines is increasingly challenging due to associated time and cost of production as well as emerging drug-resistant strains. A computer-aided vaccine design strategy is presented that could greatly accelerate the discovery process and yield vaccines with high immunogenicity and thermal stability. Our strategy is based on foreign viral epitopes engineered onto well-established virus-like particles (VLPs) and demonstrates that such constructs present similar affinity for antibodies as does a native virus.

Variational methods for time-dependent classical many-particle systems.

A variational method for the classical Liouville equation is introduced that facilitates the development of theories for non-equilibrium classical systems. The method is based on the introduction of a complex-valued auxiliary quantity Ψ that is related to the classical position-momentum probability density ρ via ρ = ΨΨ. A functional of Ψ is developed whose extrema imply that ρ satisfies the Liouville equation.

Hierarchical Order Parameters for Macromolecular Assembly Simulations I: Construction and Dynamical Properties of Order Parameters.

Macromolecular assemblies often display a hierarchical organization of macromolecules or their sub-assemblies. 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.

Electrophysiological-metabolic modeling of microbes: applications in fuel cells and environment analysis.

A formalism for simulating coupled metabolic and electrophysiological processes is presented. The resulting chemical kinetic and electrophysiological equations are solved numerically to create a cell simulator. Metabolic features of this simulator were adapted from Karyote, a multi-compartment biochemical cell modeling simulator.

Discovering free energy basins for macromolecular systems via guided multiscale simulation.

An approach for the automated discovery of low free energy states of macromolecular systems is presented. The method does not involve delineating the entire free energy landscape but proceeds in a sequential free energy minimizing state discovery; i.e.

Nanosystem self-assembly pathways discovered via all-atom multiscale analysis.

We consider the self-assembly of composite structures from a group of nanocomponents, each consisting of particles within an N-atom system. Self-assembly pathways and rates for nanocomposites are derived via a multiscale analysis of the classical Liouville equation. From a reduced statistical framework, rigorous stochastic equations for population levels of beginning, intermediate, and final aggregates are also derived.

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.

A molecular dynamics study of loop fluctuation in human papillomavirus type 16 virus-like particles: a possible indicator of immunogenicity.

Immunogenicity varies between the human papillomavirus (HPV) L1 monomer assemblies of various sizes (e.g., monomers, pentamers or whole capsids).