10, 19 The pseudo-rotation and the coupled change in substituent orientation These canonical forms are not “unique”,Īs the pseudo-rotation leads to multiple equivalent conformations,įor example, the 4 C 1 and 1 C 4 chair conformations in cyclohexane. Into different canonical forms and are usually low-energy conformations Ī classic example is the chair and boat conformations in 6-membered Typically, the ring puckers can be classified We have therefore carried out an extensive conformationalĪnalysis on a wide range of ring molecules, including cyclic peptides.įlexible rings can adopt different conformations due to out-of-planeīending motions, caused by changes in the rotatable ring bonds, resulting Rings, 9− 12 cycloalkanes, 13− 15 and families of macrocycles involved in host–guestĬhemistry, 16− 18 resulting in a lack of general understanding of ringĬonformational preferences, especially for medium-sized rings and 5− 8 The flexibility of cyclic molecules improves their chance to adoptįavorable conformations that will bind to targets with flat surfaces.ĭespite the importance of ring conformations, most studies on ringĬonformations focus on small subsets, for example, on carbohydrate Less druggable targets, e.g., mimicking protein–protein interactions. (CPs) have recently demonstrated their potential in modulating traditionally 2− 4 On the other hand, macrocycles including cyclic peptides Preferences of macrocyclic rings lead to selective complexation of In host–guest chemistry, the conformational Macrocycle conformations are crucial in host–guest chemistryĪnd drug design. For instance, the glycosidase reactions heavily depend Ring conformations for applications from polymeric materials to drugĪn important role in chemistry and biology,Īnd their shapes are intimately linked to their physical and chemical Preferences, which will in turn accelerate the identification of low-energy Work provides an improved understanding of general ring puckering Motion to generate ring conformations efficiently. Sampling method using the puckering preferences and coupled substituent Beyond ring puckers, our models also explain the change in To torsion space, which allows us to understand the inter-relatedĬhanges in torsion angles during pseudo-rotation and other puckering More importantly, we propose models to map puckering preferences Ring puckering motions,Įspecially pseudo-rotations, are generally restricted and differ betweenĬlusters. The number of such canonicalĬlusters increases slowly with ring size. By standardizing using key atoms, we show that the ringĬonformations can be classified into relatively few conformationalĬlusters, based on their canonical forms. To study the trends of the ring conformation across a set of 140 000ĭiverse small molecules, including small rings, macrocycles, and cyclic We used Cremer–Pople puckering coordinates To address this, we provide an extensive conformational analysis ofĪ diverse set of rings. Of the puckering preferences of medium-sized rings and macrocycles. Despite its importance, thereĪre relatively few studies on ring puckering and conformations, oftenįocused on small cycloalkanes, 5- and 6-membered carbohydrate rings,Īnd specific macrocycle families. Geometry of a molecule plays a significant role in determining
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