Understanding Ring Puckering in Small Molecules and Cyclic Peptides

The geometry of a molecule plays a significant role in determining its physical and chemical properties. Despite its importance, there are relatively few studies on ring puckering and conformations, often focused on small cycloalkanes, five- and six-membered carbohydrate rings and specific macrocycle families. We lack a general understanding of the puckering preferences of medium-sized rings and macrocycles. To address this, we provide an extensive conformational analysis of a diverse set of rings. We used Cremer-Pople puckering coordinates to study the trends of the ring conformation across a set of 140,000 diverse small molecules, including small rings, macrocycles and cyclic peptides. By standardizing using key atoms, we show that the ring conformations can be classified into relatively few conformational clusters, based on their canonical forms. The number of such canonical clusters increases slowly with ring size. Ring puckering motions, especially pseudo-rotations, are generally restricted, and differ between clusters. More importantly, we propose models to map puckering preferences to torsion space, which allows us to understand the interrelated changes in torsion angles during pseudo-rotation and other puckering motions. Beyond ring puckers, our models also explain the change in substituent orientation upon puckering. In summary, this work provides an improved understanding of general ring puckering preferences, which will in turn accelerate the identification of low energy ring conformations for applications from polymeric materials to drug binding.