Cooperative Capture Synthesis of Functionalized Heterorotaxanes─Chemical Scope, Kinetics, and Mechanistic Studies

The self-assembly of molecularly interlocked molecules offers new opportunities for creating bioactive molecules for applications in medicine. Cooperative capture synthesis of heterorotaxanes in water is an attractive methodology for developing multifunctional supramolecular imaging agents or drugs, but derivatizing the rotaxane scaffold with biologically active vectors like peptides and proteins, or reporter probers like radioactive metal ion complexes and fluorophores, requires the installation of reactive functional groups. Here, we explored the chemical scope of β-cyclodextrin (β-CD) derivatization on the cucurbit[6]uril (CB[6])-mediated cooperative capture synthesis of hetero[4]rotaxanes with the objective of identifying which reactive groups can be used for further functionalization without compromising the efficiency of rotaxane synthesis. Nine β-CD derivatives featuring an electrophilic leaving group (tosylate), aliphatic amines, a carboxylic acid, aliphatic azides, anilines, and aryl isothiocyanate were evaluated in the synthesis of hetero[4]rotaxanes. Experimental measurements on the kinetics of rotaxane synthesis were combined with detailed computational studies using the density functional theory to elucidate the mechanistic pathways and rate determining step in the cooperative capture process. Computational studies on the structure and bonding also revealed why intermolecular interactions between the β-CD and CB[6] macrocycles improve the rate and efficiency of rotaxane formation through cooperative capture. Understanding the mechanistic details and synthetic scope will facilitate broader access to functionalized hetero[4]rotaxanes for applications in biomedicine and beyond

Cooperative catalysis by silica-supported organic functional groups

Hybrid inorganic–organic materials comprising organic functional groups tethered from silica surfaces are versatile, heterogeneous catalysts. Recent advances have led to the preparation of silica materials containing multiple, different functional groups that can show cooperative catalysis; that is, these functional groups can act together to provide catalytic activity and selectivity superior to what can be obtained from either monofunctional materials or homogeneous catalysts. This tutorial review discusses cooperative catalysis of silica-based catalytic materials, focusing on the cooperative action of acid–base, acid–thiol, amine–urea, and imidazole–alcohol–carboxylate groups. Particular attention is given to the effect of the spatial arrangement of these organic groups and recent developments in the spatial organization of multiple groups on the silica surface

Hiding variables when decomposing specifications into GR(1) contracts

We propose a method for eliminating variables from component specifications during the decomposition of GR(1) properties into contracts. The variables that can be eliminated are identified by parameterizing the communication architecture to investigate the dependence of realizability on the availability of information. We prove that the selected variables can be hidden from other components, while still expressing the resulting specification as a game with full information with respect to the remaining variables. The values of other variables need not be known all the time, so we hide them for part of the time, thus reducing the amount of information that needs to be communicated between components. We improve on our previous results on algorithmic decomposition of GR(1) properties, and prove existence of decompositions in the full information case. We use semantic methods of computation based on binary decision diagrams. To recover the constructed specifications so that humans can read them, we implement exact symbolic minimal covering over the lattice of integer orthotopes, thus deriving minimal formulae in disjunctive normal form over integer variable intervals

Reactive concurrent programming revisited

In this note we revisit the so-called reactive programming style, which evolves from the synchronous programming model of the Esterel language by weakening the assumption that the absence of an event can be detected instantaneously. We review some research directions that have been explored since the emergence of the reactive model ten years ago. We shall also outline some questions that remain to be investigated

How to Handle Assumptions in Synthesis

The increased interest in reactive synthesis over the last decade has led to many improved solutions but also to many new questions. In this paper, we discuss the question of how to deal with assumptions on environment behavior. We present four goals that we think should be met and review several different possibilities that have been proposed. We argue that each of them falls short in at least one aspect.Comment: In Proceedings SYNT 2014, arXiv:1407.493

Steric trapping reveals a cooperativity network in the intramembrane protease GlpG.

Membrane proteins are assembled through balanced interactions among proteins, lipids and water. Studying their folding while maintaining the native lipid environment is necessary but challenging. Here we present methods for analyzing key elements of membrane protein folding including thermodynamic stability, compactness of the unfolded state and folding cooperativity under native conditions. The methods are based on steric trapping, which couples the unfolding of a doubly biotinylated protein to the binding of monovalent streptavidin (mSA). We further advanced this technology for general application by developing versatile biotin probes possessing spectroscopic reporters that are sensitized by mSA binding or protein unfolding. By applying these methods to the Escherichia coli intramembrane protease GlpG, we elucidated a widely unraveled unfolded state, subglobal unfolding of the region encompassing the active site, and a network of cooperative and localized interactions to maintain stability. These findings provide crucial insights into the folding energy landscape of membrane proteins

Lazy Abstraction-Based Controller Synthesis

We present lazy abstraction-based controller synthesis (ABCS) for continuous-time nonlinear dynamical systems against reach-avoid and safety specifications. State-of-the-art multi-layered ABCS pre-computes multiple finite-state abstractions of varying granularity and applies reactive synthesis to the coarsest abstraction whenever feasible, but adaptively considers finer abstractions when necessary. Lazy ABCS improves this technique by constructing abstractions on demand. Our insight is that the abstract transition relation only needs to be locally computed for a small set of frontier states at the precision currently required by the synthesis algorithm. We show that lazy ABCS can significantly outperform previous multi-layered ABCS algorithms: on standard benchmarks, lazy ABCS is more than 4 times faster