A High-Throughput Platform for Efficient Exploration of Functional polypeptides Chemical Space

Abstract

Rapid and in-depth exploration of the chemical space of high molecular weight synthetic polypeptides via the ring-opening polymerization (ROP) of N-carboxyanhydride (NCA) is a viable approach towards protein mimics and functional biomaterials. The traditional synthetic workflow, however, has been labour-intensive and with limited throughput. Here, we develop an efficient chemistry for the high throughput diversification of polypeptides based on a click-like reaction between selenolate and various electrophiles in aqueous solutions. Importantly, the platform is amenable to automation, which allows rapid generation of up to 1200 homopolypeptides or random heteropolypeptides (RHP) within one day. With the assistance of machine learning, iterative exploration of the RHP library efficiently and effectively identifies candidates with improved glutathione peroxidase-like activity from complex chemical space of which we have little prior knowledge. This automated and high-throughput platform provides potential solutions to unmet challenges such as de novo design of artificial enzyme, biomacromolecule delivery, and understanding of intrinsically disordered proteins.

Visible-light-driven PCy3-promoted deselenization of 1,2-diselenides

“…It was found that steric hindrance did not affect the reaction efficiency, as demonstrated by the formation of 4 and 5 in excellent yields. Dialkyl diselenides were also applicable to this transformation, and symmetrical dialkyl monoselenides were obtained in 60%-95% yields (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Various functionalities (e.g., halogen, ester, nitrile, ether, alkyne and alkene) were well tolerated, showcasing the robustness of this protocol.…”

“…[21][22][23][24][25] The oxidant-induced selenoxide elimination as a key step has found wide applications in the total synthesis of drugs and natural products. [26][27][28][29] The subsequent development of reductive systems such as Ph 3 SnH, 30 LiBHEt 3 , 31 Fig. 1 Selected important organoselenium compounds.…”

Data-Driven Design of Polymer-Based Biomaterials: High-throughput Simulation, Experimentation, and Machine Learning

“…While certain synthetic conditions might produce roughly alternating, gradient, or block structures, the precise arrangement of constitutional units within any given macromolecule is unknown, and there will be a distribution of structures produced. 104 Despite the inherent ambiguity, there is considerable interest in the surrogate modeling of such copolymers as they are also the most likely to be experimentally synthesized in quantities amenable to machine learning, 17,18,69,105 at least in the near-term. In recognition that polymers are stochastic molecules that constitute an ensemble of structures, Lin and co-workers have extended the simplified molecular-input line-entry system into the BigSMILES language, which can describe polymers of varying chemistry and architectures.…”

“…While certain synthetic conditions might produce roughly alternating, gradient, or block structures, the precise arrangement of constitutional units within any given macromolecule is unknown, and there will be a distribution of structures produced . Despite the inherent ambiguity, there is considerable interest in the surrogate modeling of such copolymers as they are also the most likely to be experimentally synthesized in quantities amenable to machine learning, ,,, at least in the near-term. In recognition that polymers are stochastic molecules that constitute an ensemble of structures, Lin and co-workers have extended the simplified molecular-input line-entry system into the BigSMILES language, which can describe polymers of varying chemistry and architectures. , In principle, BigSMILES strings or other syntactical approaches augmented with other relevant information (e.g., average mole fractions of consitutional units) might be tokenized or processed into numerical encodings for machine learning in a manner similar to small molecules, but there are few demonstrations of syntax-directed machine learning for copolymers.…”

Chirality-governed Clusteroluminescence in Polypeptides

“…[22][23][24] More importantly, polypeptides can be synthesized from Ncarboxyanhydride (NCA) ring-opening polymerization in kilogram-scale and offer considerable chemical diversity of side groups. [25][26][27][28][29][30] Fluorescent polypeptides, possessing the similar primary and secondary structures as uorescent proteins, are the ideal candidates for the applications as biomedical uorescent probes. In the last few years, CL was observed among synthetic polypeptides.…”