Practical computational toolkits for dendrimers and dendrons structure design

Dendrimers and dendrons offer an excellent platform for developing novel drug delivery systems and medicines. The rational design and further development of these repetitively branched systems are restricted by difficulties in scalable synthesis and structural determination, which can be overcome by judicious use of molecular modelling and molecular simulations. A major difficulty to utilise in silico studies to design dendrimers lies in the laborious generation of their structures. Current modelling tools utilise automated assembly of simpler dendrimers or the inefficient manual assembly of monomer precursors to generate more complicated dendrimer structures. Herein we describe two novel graphical user interface (GUI) toolkits written in Python that provide an improved degree of automation for rapid assembly of dendrimers and generation of their 2D and 3D structures. Our first toolkit uses the RDkit library, SMILES nomenclature of monomers and SMARTS reaction nomenclature to generate SMILES and mol files of dendrimers without 3D coordinates. These files are used for simple graphical representations and storing their structures in databases. The second toolkit assembles complex topology dendrimers from monomers to construct 3D dendrimer structures to be used as starting points for simulation using existing and widely available software and force fields. Both tools were validated for ease-of-use to prototype dendrimer structure and the second toolkit was especially relevant for dendrimers of high complexity and size.Peer reviewe

Nanocrystal Core Size and Shape Substitutional Doping and Underlying Crystalline Order in Nanocrystal Superlattices

Substitutional doping is a potentially powerful technique to control the properties of nanocrystal (NC) superlattices (SLs). However, not every NC can be substituted into any lattice, as the NCs have to be close in size and shape, limiting the application of substitutional doping. Here we show that this limitation can be overcome by employing ligands of various size. We show that small NCs with long ligands can be substituted into SLs of big NCs with short ligands. Furthermore, we show that shape differences can also be overcome and that cubes can substitute spheres when both are coated with long ligands. Finally, we use the NC effective ligand size, softness, and effective overall size ratio to explain observed doping behaviors

Design, Self-Assembly, and Switchable Wettability in Hydrophobic, Hydrophilic, and Janus Dendritic Ligand–Gold Nanoparticle Hybrid Materials

Controlling nanoparticles’ (NPs) surface polarity, colloidal stability, and self-assembly into well-defined complex architectures is of paramount importance for emergent nano- and biotechnologies, and each depends strongly on the ligand shell composition and chemical nature. In this study, a series of dendritic ligands with hydrophobic, hydrophilic, and Janus surface groups was synthesized, grafted onto Au NPs, and their effects on the self-assembly behavior and surface polarity of the corresponding hybrid materials were investigated. A generalized, flexible strategy was utilized for ligand synthesis that independently introduces dendritic end groups, responsible for the surface polarity and colloidal properties, and specific surface NPs binding groups, reducing the number of synthetic steps. The dendritic ligands obtained were grafted onto NP surfaces through solution phase ligand-exchange, and the resulting NP–dendron hybrids were studied using a variety of techniques such as transmission electron microscopy, UV–vis, and small-angle X-ray scattering. When the solvent evaporation rate during self-assembly is controlled, these dendronized Au hybrids self-organize into highly ordered thin films comprised of close-packed arrays of NPs where the interparticle separation can be varied as a function of the dendritic generation and end group chemistry. Moreover, contact angle and colloidal observations revealed the strong dependence of the dendron end-group and generation on the NP surface polarity. Uniquely, the hybrid material of Au NPs and the Janus dendron exhibits controlled surface wetting, where the surface polarity is dependent on solvent exposure, revealing a surface polarity memory effect, making this material a model system for surfaces that demonstrate switchable wettability

Nanocrystal core size and shape substitutional doping and underlying crystalline order in nanocrystal superlattices

Substitutional doping is a potentially powerful technique to control the properties of nanocrystal (NC) superlattices (SLs). However, not every NC can be substituted into any lattice, as the NCs have to be close in size and shape, limiting the application of substitutional doping. Here we show that this limitation can be overcome by employing ligands of various size. We show that small NCs with long ligands can be substituted into SLs of big NCs with short ligands. Furthermore, we show that shape differences can also be overcome and that cubes can substitute spheres when both are coated with long ligands. Finally, we use the NC effective ligand size, softness, and effective overall size ratio to explain observed doping behaviors

Differential Potency of 2,6-Dimethylcyclohexanol Isomers for Positive Modulation of GABAA Receptor Currents

GABAA receptors meet all of the pharmacological requirements necessary to be considered important targets for the action of general anesthetic agents in the mammalian brain. In the following patch-clamp study, the relative modulatory effects of 2,6-dimethylcyclohexanol diastereomers were investigated on human GABAA (a1b3g2s) receptor currents stably expressed in human embryonic kidney cells. Cis,cis-, trans,trans-, and cis, trans-isomers were isolated from commercially available 2,6- dimethylcyclohexanol and were tested for positive modulation of submaximal GABA responses. For example, the addition of 30 mM cis,cis-isomer resulted in an approximately 2- to 3-fold enhancement of the EC20 GABA current. Coapplications of 30 mM 2,6-dimethylcyclohexanol isomers produced a range of positive enhancements of control GABA responses with a rank order for positive modulation: cis,cis . trans,trans $ mixture of isomers . . cis,transisomer. In molecular modeling studies, the three cyclohexanol isomers bound with the highest binding energies to a pocket within transmembrane helices M1 and M2 of the b3 subunit through hydrogen-bonding interactions with a glutamine at the 224 position and a tyrosine at the 220 position. The energies for binding to and hydrogen-bond lengths within this pocket corresponded with the relative potencies of the agents for positive modulation of GABAA receptor currents (cis,cis . trans,trans . cis,trans-2,6-dimethylcyclohexanol). In conclusion, the stereochemical configuration within the dimethylcyclohexanols is an important molecular feature in conferring positive modulation of GABAA receptor activity and for binding to the receptor, a consideration that needs to be taken into account when designing novel anesthetics with enhanced therapeutic indices