Understanding Ring Puckering in Small Molecules and Cyclic Peptides.

Area of Science:

• Computational Chemistry
• Molecular Modeling
• Structural Chemistry

Background:

• Molecular geometry dictates physical and chemical properties.
• Limited understanding of puckering in medium-sized rings and macrocycles.
• Existing studies often focus on small rings or specific families.

Purpose of the Study:

• To provide a general understanding of ring puckering preferences in diverse molecules.
• To classify ring conformations and analyze puckering motions.
• To develop models for predicting and generating ring conformations.

Main Methods:

• Utilized Cremer-Pople puckering coordinates for conformational analysis.
• Analyzed a dataset of 140,000 diverse small molecules, macrocycles, and cyclic peptides.
• Developed models to map puckering preferences to torsion space and coupled substituent motion.

Main Results:

• Identified a few canonical conformational clusters for ring structures.
• Showed that the number of clusters increases slowly with ring size.
• Demonstrated restricted ring puckering motions and distinct behaviors across clusters.
• Proposed models explaining substituent orientation changes during puckering.

Conclusions:

• Established a general framework for understanding ring puckering preferences.
• Developed an efficient knowledge-based sampling method for conformation generation.
• The findings will accelerate the identification of low-energy conformations for materials and drug discovery.