EnzymeRSI: A dual-loop recursive self-improvement system for enzyme design
Genoria AI Team, Yuejie Hou, Lixiang Yang, Yisi Liu, Weiting Tang, Yueyuxiao Yang, Meng Yang
Improvement in enzyme engineering is usually pursued by optimising which candidates to assay within a fixed model and workflow; when the bottleneck arises from a mismatched method or a failing workflow, that route is difficult to escape. We present EnzymeRSI, a dual-loop system for recursive self-improvement (RSI). The outer loop evolves harness assets without changing model weights, the inner loop develops prediction and selection algorithms under controlled conditions, and a cloud laboratory system is specified to close the physical loop with quality-controlled feedback. By updating its prediction strategy through iterative comparison, the outer loop raised the mean development-set Spearman correlation on ProteinGym by 0.044 across five assays, reaching 0.335 on CD19 and 0.683 on OPSD (rhodopsin); of the two first places, only CD19 was produced by the outer loop itself. In the self-improvement of the ThermoMPNN algorithm the inner loop reached a PCC of 0.849, and on TadA-Bench it reached a Spearman correlation of 0.307 in 1.13 h. In three prospective wet-lab tests of the system's experimental decision-making, 10 of the 32 candidates that had not been pre-specified for the luciferase RLuc showed at least twice the wild-type activity; a recommended variant of the cytidine deaminase A3A raised 5mC conversion to 90.2%; and path selection in evolution raised the catalytic efficiency of the DNA polymerase KOD-E on a modified substrate to 31.1 times that of the parent. By treating the organisation of the research workflow and the development of algorithms as a single falsifiable dry-to-wet loop, this work offers an evolutionary paradigm for moving beyond the blind spots of a fixed method and for autonomous enzyme engineering.
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