Design of Multivalent Inhibitors for Preventing Cellular Uptake.

Cellular entry, the first crucial step of viral infection, can be inhibited by molecules adsorbed on the virus surface. However, apart from using stronger affinity, little is known about the properties of such inhibitors that could increase their effectiveness. Our simulations showed that multivalent inhibitors can be designed to be much more efficient than their monovalent counterparts.

Influence of ligand distribution on uptake efficiency.

Cellular uptake is a crucial process in nanomedicine and drug-delivery; however, the factors that affect its efficiency/speed are not well understood. We report computer simulations on passive uptake via receptor-mediated endocytosis of nanoparticle coated with ligands. In particular, we study how the distribution of ligands on the nanoparticle surface influences the uptake rate.

Nanoparticle organization in sandwiched polymer brushes.

The organization of nanoparticles inside grafted polymer layers is governed by the interplay of polymer-induced entropic interactions and the action of externally applied fields. Earlier work had shown that strong external forces can drive the formation of colloidal structures in polymer brushes. Here we show that external fields are not essential to obtain such colloidal patterns: we report Monte Carlo and molecular dynamics simulations that demonstrate that ordered structures can be achieved by compressing a "sandwich" of two grafted polymer layers, or by squeezing a coated nanotube, with nanoparticles in between.

Designing stimulus-sensitive colloidal walkers.

Colloidal particles with DNA "legs" that can bind reversibly to receptors on a surface can be made to 'walk' if there is a gradient in receptor concentration. We use a combination of theory and Monte Carlo simulations to explore how controllable parameters, e.g.

Spatiotemporal control and superselectivity in supramolecular polymers using multivalency.

Multivalency has an important but poorly understood role in molecular self-organization. We present the noncovalent synthesis of a multicomponent supramolecular polymer in which chemically distinct monomers spontaneously coassemble into a dynamic, functional structure. We show that a multivalent recruiter is able to bind selectively to one subset of monomers (receptors) and trigger their clustering along the self-assembled polymer, behavior that mimics raft formation in cell membranes.

Intracellular release of endocytosed nanoparticles upon a change of ligand-receptor interaction.

During passive endocytosis, nanosized particles are initially encapsulated by a membrane separating it from the cytosol. Yet, in many applications the nanoparticles need to be in direct contact with the cytosol in order to be active. We report a simulation study that elucidates the physical mechanisms by which such nanoparticles can shed their bilayer coating.

Quantitative prediction of the phase diagram of DNA-functionalized nanosized colloids.

We present a coarse-grained model of DNA-functionalized colloids that is computationally tractable. Importantly, the model parameters are solely based on experimental data. Using this highly simplified model, we can predict the phase behavior of DNA-functionalized nanocolloids without assuming pairwise additivity of the intercolloidal interactions.

A theoretical and simulation study of the self-assembly of a binary blend of diblock copolymers.

Pure diblock copolymer melts exhibit a narrow range of conditions at which bicontinuous and cocontinuous phases are stable; such conditions and the morphology of such phases can be tuned by the use of additives. In this work, we have studied a bidisperse system of diblock copolymers using theory and simulation. In particular, we elucidated how a short, lamellar-forming diblock copolymer modifies the phase behavior of a longer, cylinder-forming diblock copolymer.

Layering, freezing, and re-entrant melting of hard spheres in soft confinement.

Confinement can have a dramatic effect on the behavior of all sorts of particulate systems, and it therefore is an important phenomenon in many different areas of physics and technology. Here, we investigate the role played by the softness of the confining potential. Using grand canonical Monte Carlo simulations, we determine the phase diagram of three-dimensional hard spheres that in one dimension are constrained to a plane by a harmonic potential.

Receptor-mediated endocytosis of nanoparticles of various shapes.

Cellular uptake through endocytosis is crucial for drug delivery and nanomedicine. However, the conditions under which passive endocytosis (i.e.

Design rule for colloidal crystals of DNA-functionalized particles.

We report a Monte Carlo simulation study of the phase behavior of colloids coated with long, flexible DNA chains. We find that an important change occurs in the phase diagram when the number of DNAs per colloid is decreased below a critical value. In this case, the triple point disappears and the condensed phase that coexists with the vapor is always liquid.

Designing super selectivity in multivalent nano-particle binding.

A key challenge in nano-science is to design ligand-coated nano-particles that can bind selectively to surfaces that display the cognate receptors above a threshold (surface) concentration. Nano-particles that bind monovalently to a target surface do not discriminate sharply between surfaces with high and low receptor coverage. In contrast, "multivalent" nano-particles that can bind to a larger number of ligands simultaneously, display regimes of "super selectivity" where the fraction of bound particles varies sharply with the receptor concentration.

Optimization of expanded ensemble methods.

Expanded ensemble methods, designed to sample a range of an order parameter lambda of interest, can be optimized to overcome the difficulties associated with traversing large free-energy barriers or rugged landscapes. The optimization strategy of Trebst et al. [Phys.

Variance minimization of free energy estimates from optimized expanded ensembles.

We explored the possibility of improving the accuracy and precision of free-energy differences estimated via expanded ensembles by manipulation of the biasing weights. Three different weighing approaches were compared: the flat histogram (FH) method, the optimized ensemble (OE) method, and a method introduced in this work, denoted MinVar, which aims to explicitly minimize the expected variance. The performance of these three methods was tested for the simulation of chemical potentials in systems of symmetric diblock copolymers with chain lengths of either 10 or 4 beads, and a system of one large hard sphere of diameter 10 d immersed in a fluid of hard spheres of diameter d.

Optimized expanded ensembles for simulations involving molecular insertions and deletions. I. Closed systems.

Monte Carlo simulation methods that involve the insertion-deletion of molecules are of wide spread use for the study of thermophysical behavior of complex systems; e.g., for the estimation of chemical potentials in closed-system ensembles.

Simulation of the gyroid phase in off-lattice models of pure diblock copolymer melts.

Particle-based molecular simulations of pure diblock copolymer (DBC) systems were performed in continuum space via dissipative particle dynamics and Monte Carlo methods for a bead-spring chain model. This model consisted of chains of soft repulsive particles often used with dissipative particle dynamics. The gyroid phase was successfully simulated in DBC melts at selected conditions provided that the simulation box size was commensurate with the gyroid lattice spacing.

Protein translocation through a tunnel induces changes in folding kinetics: a lattice model study.

Compaction of a nascent polypeptide chain inside the ribosomal exit tunnel, before it leaves the ribosome, has been proposed to accelerate the folding of newly synthesized proteins following their release from the ribosome. Thus, we used Kinetic Monte Carlo simulations of a minimalist on-lattice model to explore the effect that polypeptide translocation through a variety of channels has on protein folding kinetics. Our results demonstrate that tunnel confinement promotes faster folding of a well-designed protein relative to its folding in free space by displacing the unfolded state towards more compact structures that are closer to the transition state.