High-Throughput Computational Evaluation of Low Symmetry Pd2L4 Cages to Aid in System Design

Molecular cages have potential as enzyme-mimics and in applications such as catalysis, drug-delivery and sensing.  Recently, chemists have attempted to introduce more complexity into their structures in an attempt to emulate Nature’s success with proteins and enzymes. However, it can be difficult for researchers to design complex cages from scratch.

In particular, the introduction of unsymmetrical components (Figure 1) leads to side-reactions and undesired products during the cage formation reaction, which leads to wasted experimental efforts. In this work, we used a computer-driven approach to predict the likely outcome of the cage reaction, which guided the selection of ideal building blocks to test experimentally. We use low-cost computational methods such that many candidates can be evaluated computationally in a short amount of time on a standard computer. From this large pool of candidates, we selected a number of building blocks for synthesis, which lead to the formation of several new “wonky cages”. Additionally, the results validated the applicability of the joint computational and experimental workflow.