Natural enzymes contain highly evolved active sites that lead to fast rates and high selectivities. Although artificial metalloenzymes have been developed that catalyze abiological transformations with high stereoselectivity, the activities of these artificial enzymes are much lower than those of natural enzymes. Here, we report a reconstituted artificial metalloenzyme containing an iridium porphyrin that exhibits kinetic parameters similar to those of natural enzymes. This activity leads to intramolecular carbene insertions into unactivated C–H bonds and intermolecular carbene insertions into C–H bonds. These results lift the restrictions on merging chemical catalysis and biocatalysis to create highly active, productive, and selective metalloenzymes for abiological reactions.
A peg-in-hole insertion task is used as an example to illustrate the utility of direct associative reinforcement learning methods for learning control under real-world conditions of uncertainty and noise. Task complexity due to the use of an unchamfered hole and a clearance of less than 0.2mm is compounded by the presence of positional uncertainty of magnitude exceeding 10 to 50 times the clearance. Despite this extreme degree of uncertainty, our results indicate that direct reinforcement learning can be used to learn a robust reactive control strategy that results in skillful peg-in-hole insertions.
Membrane proteins make up one-quarter of the human proteome and are required for all aspects of cell-to-cell communication, signaling, and transport. Defects in membrane protein biogenesis underlie a variety of human diseases, and half of all therapeutic drugs target an integral membrane protein. Pleiner et al. describe the cryo–electron microscopy structure of the human endoplasmic reticulum (ER) membrane protein complex, a large oligomeric assembly involved in the biogenesis of membrane proteins in the ER. This structure helps to explain how this complex captures and then inserts nascent proteins into the lipid bilayer, elucidating the molecular details of a fundamental biological process with broad biomedical implications. Science , this issue p.  A defining step in the biogenesis of a membrane protein is the insertion of its hydrophobic transmembrane helices into the lipid bilayer. The nine-subunit endoplasmic reticulum (ER) membrane protein complex (EMC) is a conserved co- and posttranslational insertase at the ER. We determined the structure of the human EMC in a lipid nanodisc to an overall resolution of 3.4 angstroms by cryo–electron microscopy, permitting building of a nearly complete atomic model. We used structure-guided mutagenesis to demonstrate that substrate insertion requires a methionine-rich cytosolic loop and occurs via an enclosed hydrophilic vestibule within the membrane formed by the subunits EMC3 and EMC6. We propose that the EMC uses local membrane thinning and a positively charged patch to decrease the energetic barrier for insertion into the bilayer. : /lookup/doi/10.1126/science.abb5008