Multivalent binding and selectivity in cell targeting, molecular recognition and receptor activation

MULTIVALENT BINDING AND SELECTIVITY IN CELL TARGETING, MOLECULAR RECOGNITION AND RECEPTOR ACTIVATION Jure Dobnikar, Institute of Physics, Chinese Academy of Sciences, Beijing, Chin ; Department of Chemistry, University of Cambridge, UK ; School of physical sciences, University of Chinese Academy of Sciences One of the key challenges in nano-science is to design nanoparticles that can recognize and target specific objects. One such example are ligand-coated nanoparticles binding to surfaces covered with receptors forming bonds with the ligands. The requirement of many applications is that the particles bind selectively to surfaces with receptors either above a threshold concentration or in a specific geometric arrangement. Such nanoparticles would enable precise functioning of nano machines, as well as selective targeting of cells in drug delivery. Similarly, many biological processes rely on chemical activation based on (macro-) molecular recognition. Also in this case, the receptors need to selectively bind to specific molecules to get activated. In recent years, it has been shown that super-selectivity can only be achieved with multiple weak reversible bonds where many ligands simultaneously bind to the surface receptors. Only in such systems, the fraction of bound particles varies sharply with the receptor concentration and nano-particles can be designed such that they approach the on-off binding behaviour required for super- selective targeting. I will report on our recent work on physics of multivalent binding and specifically address targeting cancer cells, molecular recognition and multivalent receptor activation by DNA-peptide complexes in the immune system. Publications: [1] N.W. Schmidt, F. Jin, R. Lande, T. Curk, W. Xian, L. Frasca, D. Frenkel, J. Dobnikar, M. Gilliet, G.C.L. Wong, Antimicrobial-peptide-DNA complexes amplify TLR9 activation via liquid-crystalline ordering, Nature Materials 14, 696 (2015) [2] T. Curk, J. Dobnikar, D. Frenkel, Rational design of molecularly imprinted polymers, Soft Matter 12, 35 (2016) [3] T. Curk, J. Dobnikar, and D. Frenkel, Optimal multivalent targeting of mem- branes with many distinct receptors, to appear in PNAS (2017

Phase behaviour of colloidal assemblies on 2D corrugated substrates

We investigate - with Monte Carlo computer simulations - the phase behaviour of dimeric colloidal molecules on periodic substrates with square symmetry. The molecules are formed in a two-dimensional suspension of like charged colloids subject to periodic external confinement, which can be experimentally realized by optical methods. We study the evolution of positional and orientational order by varying the temperature across the melting transition. We propose and evaluate appropriate order parameters as well as the specific heat capacity and show that the decay of positional correlations belongs to a class of crossover transitions while the orientational melting is a second-order phase transition.Comment: 13 pages, 9 figures, accepted in J. Phys.: Condens. Matte

Rational design of molecularly imprinted polymers.

Molecular imprinting is the process whereby a polymer matrix is cross-linked in the presence of molecules with surface sites that can bind selectively to certain ligands on the polymer. The cross-linking process endows the polymer matrix with a chemical 'memory', such that the target molecules can subsequently be recognized by the matrix. We present a simple model that accounts for the key features of this molecular recognition. Using a combination of analytical calculations and Monte Carlo simulations, we show that the model can account for the binding of rigid particles to an imprinted polymer matrix with valence-limited interactions. We show how the binding multivalency and the polymer material properties affect the efficiency and selectivity of molecular imprinting. Our calculations allow us to formulate design criteria for optimal molecular imprinting.This work was supported by the Fundamental Research Funds for the Central Universities of P. R. China, ERC Advanced Grant 227758 (COLSTRUCTION), ITN grant 234810 (COMPPLOIDS) and by EPSRC Programme Grant EP/I001352/1. TC acknowledges support from the Herchel Smith fund.This is the final version of the article. It first appeared from RSC via http://dx.doi.org/10.1039/C5SM02144

Nanoparticle ordering in sandwiched polymer brushes

The organization of nano-particles 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 nano-particles in between. We show that the pattern formation can be efficiently controlled by the applied pressure, while the characteristic length--scale, i.e. the typical width of the patterns, is sensitive to the length of the polymers. Based on the results of the simulations, we derive an approximate equation of state for nano-sandwiches.Comment: 18 pages, 4 figure

The Effect of Attractive Interactions and Macromolecular Crowding on Crystallins Association.

In living systems proteins are typically found in crowded environments where their effective interactions strongly depend on the surrounding medium. Yet, their association and dissociation needs to be robustly controlled in order to enable biological function. Uncontrolled protein aggregation often causes disease. For instance, cataract is caused by the clustering of lens proteins, i.e., crystallins, resulting in enhanced light scattering and impaired vision or blindness. To investigate the molecular origins of cataract formation and to design efficient treatments, a better understanding of crystallin association in macromolecular crowded environment is needed. Here we present a theoretical study of simple coarse grained colloidal models to characterize the general features of how the association equilibrium of proteins depends on the magnitude of intermolecular attraction. By comparing the analytic results to the available experimental data on the osmotic pressure in crystallin solutions, we identify the effective parameters regimes applicable to crystallins. Moreover, the combination of two models allows us to predict that the number of binding sites on crystallin is small, i.e. one to three per protein, which is different from previous estimates. We further observe that the crowding factor is sensitive to the size asymmetry between the reactants and crowding agents, the shape of the protein clusters, and to small variations of intermolecular attraction. Our work may provide general guidelines on how to steer the protein interactions in order to control their association