Conformational sampling of seven-membered rings using extended puckering collective variables in metadynamics

Abstract

Seven-membered rings, though scarce in biosynthetic pathways, are increasingly recognized as conformationally rich scaffolds for engineered enzymes and drug leads. Accurately capturing their flexibility requires the use of enhanced-sampling methods. Here we present a set of collective variables (CVs) for metadynamics simulations that extend the Cremer–Pople puckering coordinates to seven-membered rings, and we validate them on cycloheptane and other molecules of increasing complexity (buxenine-G, two azepane derivatives, and ε-caprolactone). The new CVs can be used directly in PLUMED—a popular open-source library for enhanced-sampling and free-energy methods—so they can be used directly in metadynamics workflows. They allow the investigation of conformational transitions, the identification of metastable states, and the mapping of free-energy landscapes of any seven-membered-ring molecule. This provides a quantitative framework for probing the conformational behavior of flexible seven-membered scaffolds and will aid in the rational design of conformationally locked substrates for enzyme engineering and related applications.