Improving Accuracy, Diversity, and Speed with Prime Macrocycle Conformational Sampling

A novel method for exploring macrocycle conformational space, Prime macrocycle conformational sampling (Prime-MCS), is introduced and evaluated in the context of other available algorithms (Molecular Dynamics, LowModeMD in MOE, and MacroModel Baseline Search). The algorithms were benchmarked on a data set of 208 macrocycles which was curated for diversity from the Cambridge Structural Database, the Protein Data Bank, and the Biologically Interesting Molecule Reference Dictionary. The algorithms were evaluated in terms of accuracy (ability to reproduce the crystal structure), diversity (coverage of conformational space), and computational speed. Prime-MCS most reliably reproduced crystallographic structures for RMSD thresholds >1.0 Å, most often produced the most diverse conformational ensemble, and was most often the fastest algorithm. Detailed analysis and examination of both typical and outlier cases were performed to reveal characteristics, shortcomings, expected performance, and complementarity of the methods.